Pulmonary alveolar proteinosis: Difference between revisions

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__NOTOC__
__NOTOC__
{{SI}}                                                                 
{{SI}}                                                                 
{{CMG}} {{AE}}{{MA}} [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu]  
{{CMG}} {{AE}}{{MA}} [mailto:malihash@bidmc.harvard.edu] [mailto:malihash@bidmc.harvard.edu]  
   
   
{{SK}}Pulmonary alveolar phospholipoproteinosis ; Synonym 2; Synonym 3
{{SK}}Pulmonary alveolar phospholipoproteinosis  


==Overview==
==Overview==


Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958. Pulmonary alveolar proteinosis ( PAP) may be classified into 2 subtypes, primary and secondary pulmonary alveolar proteinosis. The pathogenesis of pulmonary alveolar proteinosis is characterized by the intraalveolar accumulation of [[surfactant]] [[phospholipid]] and [[apoproteins]]. Pulmonary alveolar proteinosis develop because of reduced [[granulocyte-macrophage colony-stimulating factor]] ([[GM-CSF]]) levels or function and/or impaired alveolar macrophage function. On [[gross pathology]] after lung washings, fluid with the milky composition are the characteristic finding of pulmonary alveolar proteinosis. On microscopic histopathological analysis, [[terminal bronchioles]] and [[alveoli]] are filled with a lipoproteinaceous material that will be pink after [[Periodic acid-Schiff stain|periodic acid-Schiff (PAS) stain]]. The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with exposure to [[insecticides]], hematologic [[malignancies]], or [[HIV]] infection. Pulmonary alveolar proteinosis must be differentiated from other diseases that cause [[Ground glass opacification on CT|ground glass]] opacities in [[radiography]]. Pulmonary alveolar proteinosis is more commonly observed among patients aged 40- 50 years old. Men are more commonly affected with pulmonary alveolar proteinosis than women. Common risk factors in the development of pulmonary alveolar proteinosis are current or former cigarette smokers and [[Human Immunodeficiency Virus (HIV)|HIV]] infection. If left untreated, patients with pulmonary alveolar proteinosis may progress to develop [[pulmonary fibrosis]], [[cor pulmonale]]. Symptoms of pulmonary alveolar proteinosis may include [[dyspnea]] on exertion, [[cough]]. The physical examination is often normal. Laboratory findings are serum anti-granulocyte-macrophage colony-stimulating factor ([[GM-CSF]]) antibodies in [[autoimmune]] pulmonary alveolar proteinosis and elevated serum level of [[GM-CSF]] in [[hereditary]] pulmonary alveolar proteinosis. Imaging studies include chest x-ray and high resolution computed tomography (HRCT). Treatment include whole-lung lavage (WLL), recombinant [[Granulocyte macrophage colony stimulating factor|GM-CSF]] and lung transplantation.
==Historical Perspective==
*Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958, during pathologic investigations of material filling the alveoli. <ref name="RosenCastleman1958">{{cite journal|last1=Rosen|first1=Samuel H.|last2=Castleman|first2=Benjamin|last3=Liebow|first3=Averill A.|last4=Enzinger|first4=Frank M.|last5=Hunt|first5=Richard T. N.|title=Pulmonary Alveolar Proteinosis|journal=New England Journal of Medicine|volume=258|issue=23|year=1958|pages=1123–1142|issn=0028-4793|doi=10.1056/NEJM195806052582301}}</ref>


==Historical Perspective==
*In 1960, the first  therapeutic [[bronchoalveolar lavage]] by repeated segmental flooding was developed by Dr. Jose Ramirez-Rivera to treat pulmonary alveolar proteinosis. <ref name="Ramirez-R.Nyka1963">{{cite journal|last1=Ramirez-R.|first1=Jose|last2=Nyka|first2=Walenty|last3=McLaughlin|first3=Joseph|title=Pulmonary Alveolar Proteinosis|journal=New England Journal of Medicine|volume=268|issue=4|year=1963|pages=165–171|issn=0028-4793|doi=10.1056/NEJM196301242680401}}</ref>
*Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958 during pathologic investigations of material filling the alveoli. <ref name="RosenCastleman1958">{{cite journal|last1=Rosen|first1=Samuel H.|last2=Castleman|first2=Benjamin|last3=Liebow|first3=Averill A.|last4=Enzinger|first4=Frank M.|last5=Hunt|first5=Richard T. N.|title=Pulmonary Alveolar Proteinosis|journal=New England Journal of Medicine|volume=258|issue=23|year=1958|pages=1123–1142|issn=0028-4793|doi=10.1056/NEJM195806052582301}}</ref>
*In [year], [gene] mutations were first identified in the pathogenesis of [disease name].
*In 1960, the first  therapeutic bronchoalveolar lavage by repeated segmental flooding was developed by Dr. Jose Ramirez-Rivera to treat pulmonary alveolar proteinosis. <ref name="Ramirez-R.Nyka1963">{{cite journal|last1=Ramirez-R.|first1=Jose|last2=Nyka|first2=Walenty|last3=McLaughlin|first3=Joseph|title=Pulmonary Alveolar Proteinosis|journal=New England Journal of Medicine|volume=268|issue=4|year=1963|pages=165–171|issn=0028-4793|doi=10.1056/NEJM196301242680401}}</ref>


==Classification==
==Classification==
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====== Primary Pulmonary alveolar proteinosis: ======
====== Primary Pulmonary alveolar proteinosis: ======
:*Autoimmune and hereditary PAP: Disruption of Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling<ref name="pmid27514590">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
:*[[Autoimmune]] and [[hereditary]] PAP: Disruption of [[Granulocyte-macrophage colony-stimulating factor]] ([[GM-CSF]]) signalling<ref name="pmid27514590">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
:**Clearance of surfactant by alveolar macrophages is regulated by GM-CSF
:**Clearance of [[surfactant]] by alveolar [[Macrophage|macrophages]] is regulated by [[GM-CSF]]
:**Autoimmune PAP: The most common type of PAP in adults
:**[[Autoimmune]] PAP: The most common type of PAP in adults
:***Effect of GM-CSF on alveolar macrophages is neutralized by antibodies to GM-CSF
:***Effect of [[GM-CSF]] on alveolar [[Macrophage|macrophages]] is neutralized by [[antibodies]] to [[GM-CSF]]
:**Hereditary PAP :GM-CSF is intact but recessive variants of the GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB) impair signaling by GM-CSF
:**[[Hereditary]] PAP: GM-CSF is intact but [[recessive]] variants of the GM-CSF receptor alpha and beta genes (CSF2RA and [[CSF2RB]]) impair signaling by GM-CSF
:* Congenital PAP: Disorders of surfactant production
:* [[Congenital]] PAP: Disorders of [[surfactant]] production
:** Variants of surfactant proteins B and C (SFTPB, SFTPC)<ref name="pmid15358702">{{cite journal |vauthors=Brasch F, Birzele J, Ochs M, Guttentag SH, Schoch OD, Boehler A, Beers MF, Müller KM, Hawgood S, Johnen G |title=Surfactant proteins in pulmonary alveolar proteinosis in adults |journal=Eur. Respir. J. |volume=24 |issue=3 |pages=426–35 |date=September 2004 |pmid=15358702 |doi=10.1183/09031936.04.00076403 |url=}}</ref>
:** Variants of [[surfactant]] proteins B and C (SFTPB, SFTPC)<ref name="pmid15358702">{{cite journal |vauthors=Brasch F, Birzele J, Ochs M, Guttentag SH, Schoch OD, Boehler A, Beers MF, Müller KM, Hawgood S, Johnen G |title=Surfactant proteins in pulmonary alveolar proteinosis in adults |journal=Eur. Respir. J. |volume=24 |issue=3 |pages=426–35 |date=September 2004 |pmid=15358702 |doi=10.1183/09031936.04.00076403 |url=}}</ref>
:** Variants of ATP-binding cassette, subfamily A (ABCA3)<ref name="pmid11940594">{{cite journal |vauthors=Mulugeta S, Gray JM, Notarfrancesco KL, Gonzales LW, Koval M, Feinstein SI, Ballard PL, Fisher AB, Shuman H |title=Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3 |journal=J. Biol. Chem. |volume=277 |issue=25 |pages=22147–55 |date=June 2002 |pmid=11940594 |doi=10.1074/jbc.M201812200 |url=}}</ref>
:** Variants of [[ATP-binding cassette family|ATP-binding cassette]], subfamily A ([[ABCA3]])<ref name="pmid11940594">{{cite journal |vauthors=Mulugeta S, Gray JM, Notarfrancesco KL, Gonzales LW, Koval M, Feinstein SI, Ballard PL, Fisher AB, Shuman H |title=Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3 |journal=J. Biol. Chem. |volume=277 |issue=25 |pages=22147–55 |date=June 2002 |pmid=11940594 |doi=10.1074/jbc.M201812200 |url=}}</ref>
:** Variant of NK2 homeobox-1 (NKX2.1) <ref name="pmid23997037">{{cite journal |vauthors=Salerno T, Peca D, Menchini L, Schiavino A, Petreschi F, Occasi F, Cogo P, Danhaive O, Cutrera R |title=Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene |journal=Pediatr. Pulmonol. |volume=49 |issue=3 |pages=E42–4 |date=March 2014 |pmid=23997037 |doi=10.1002/ppul.22788 |url=}}</ref>
:** Variant of NK2 homeobox-1 (NKX2.1) <ref name="pmid23997037">{{cite journal |vauthors=Salerno T, Peca D, Menchini L, Schiavino A, Petreschi F, Occasi F, Cogo P, Danhaive O, Cutrera R |title=Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene |journal=Pediatr. Pulmonol. |volume=49 |issue=3 |pages=E42–4 |date=March 2014 |pmid=23997037 |doi=10.1002/ppul.22788 |url=}}</ref>
:** Variants in the gene SLC7A7<ref name="urlGeneReviews® - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK1116/ |title=GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}</ref><nowiki/>
:** Variants in the gene [[SLC7A7]]<ref name="urlGeneReviews® - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK1116/ |title=GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}</ref><nowiki/>
:** Variants of the MARS (Methionyl-tRNA synthetasegene ): Prevalent on Réunion Island<ref name="pmid25913036">{{cite journal |vauthors=Hadchouel A, Wieland T, Griese M, Baruffini E, Lorenz-Depiereux B, Enaud L, Graf E, Dubus JC, Halioui-Louhaichi S, Coulomb A, Delacourt C, Eckstein G, Zarbock R, Schwarzmayr T, Cartault F, Meitinger T, Lodi T, de Blic J, Strom TM |title=Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island |journal=Am. J. Hum. Genet. |volume=96 |issue=5 |pages=826–31 |date=May 2015 |pmid=25913036 |pmc=4570277 |doi=10.1016/j.ajhg.2015.03.010 |url=}}</ref>
:** Variants of the [[MARS (gene)|MARS]] (methionyl-tRNA synthetasegene ): Prevalent on Réunion Island<ref name="pmid25913036">{{cite journal |vauthors=Hadchouel A, Wieland T, Griese M, Baruffini E, Lorenz-Depiereux B, Enaud L, Graf E, Dubus JC, Halioui-Louhaichi S, Coulomb A, Delacourt C, Eckstein G, Zarbock R, Schwarzmayr T, Cartault F, Meitinger T, Lodi T, de Blic J, Strom TM |title=Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island |journal=Am. J. Hum. Genet. |volume=96 |issue=5 |pages=826–31 |date=May 2015 |pmid=25913036 |pmc=4570277 |doi=10.1016/j.ajhg.2015.03.010 |url=}}</ref>


====== Secondary pulmonary alveolar proteinosis: ======
====== Secondary pulmonary alveolar proteinosis: ======
:* High level dust exposures( titanium, silica, indium-tin oxide, aluminum)<ref name="pmid5775743">{{cite journal |vauthors=Buechner HA, Ansari A |title=Acute silico-proteinosis. A new pathologic variant of acute silicosis in sandblasters, characterized by histologic features resembling alveolar proteinosis |journal=Dis Chest |volume=55 |issue=4 |pages=274–8 |date=April 1969 |pmid=5775743 |doi= |url=}}</ref>
:* High level dust exposures ([[titanium]], [[silica]], indium-tin oxide, [[aluminum]])<ref name="pmid5775743">{{cite journal |vauthors=Buechner HA, Ansari A |title=Acute silico-proteinosis. A new pathologic variant of acute silicosis in sandblasters, characterized by histologic features resembling alveolar proteinosis |journal=Dis Chest |volume=55 |issue=4 |pages=274–8 |date=April 1969 |pmid=5775743 |doi= |url=}}</ref>
:* Hematologic dyscrasias such as GATA2 gene deficiency, myelodysplastic syndrome and hematologic malignancy <ref name="pmid8118651">{{cite journal |vauthors=Cordonnier C, Fleury-Feith J, Escudier E, Atassi K, Bernaudin JF |title=Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients |journal=Am. J. Respir. Crit. Care Med. |volume=149 |issue=3 Pt 1 |pages=788–94 |date=March 1994 |pmid=8118651 |doi=10.1164/ajrccm.149.3.8118651 |url=}}</ref>
:* Hematologic [[dyscrasias]] such as [[GATA2]] gene deficiency, [[myelodysplastic syndrome]] and [[hematologic malignancy]] <ref name="pmid8118651">{{cite journal |vauthors=Cordonnier C, Fleury-Feith J, Escudier E, Atassi K, Bernaudin JF |title=Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients |journal=Am. J. Respir. Crit. Care Med. |volume=149 |issue=3 Pt 1 |pages=788–94 |date=March 1994 |pmid=8118651 |doi=10.1164/ajrccm.149.3.8118651 |url=}}</ref>
:* After allogeneic hematopoietic cell transplantation for myeloid malignancies <ref name="pmid16162733">{{cite journal |vauthors=Sharma S, Nadrous HF, Peters SG, Tefferi A, Litzow MR, Aubry MC, Afessa B |title=Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings |journal=Chest |volume=128 |issue=3 |pages=1385–92 |date=September 2005 |pmid=16162733 |doi=10.1378/chest.128.3.1385 |url=}}</ref>
:* After [[allogeneic]] hematopoietic cell [[transplantation]] for myeloid malignancies <ref name="pmid16162733">{{cite journal |vauthors=Sharma S, Nadrous HF, Peters SG, Tefferi A, Litzow MR, Aubry MC, Afessa B |title=Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings |journal=Chest |volume=128 |issue=3 |pages=1385–92 |date=September 2005 |pmid=16162733 |doi=10.1378/chest.128.3.1385 |url=}}</ref>


==Pathophysiology==
==Pathophysiology==
*The pathogenesis of pulmonary alveolar proteinosis is characterized by the intraalveolar accumulation of surfactant phospholipid and apoproteins. Pulmonary alveolar proteinosis develop because of reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) levels or function and/or impaired alveolar macrophage function.<ref name="pmid20338813">{{cite journal |vauthors=Carey B, Trapnell BC |title=The molecular basis of pulmonary alveolar proteinosis |journal=Clin. Immunol. |volume=135 |issue=2 |pages=223–35 |date=May 2010 |pmid=20338813 |pmc=2866141 |doi=10.1016/j.clim.2010.02.017 |url=}}</ref>   
*The pathogenesis of pulmonary alveolar proteinosis is characterized by the intraalveolar accumulation of [[surfactant]] [[phospholipid]] and [[apoproteins]]. Pulmonary alveolar proteinosis develop because of reduced [[granulocyte-macrophage colony-stimulating factor]] ([[GM-CSF]]) levels or function and/or impaired alveolar macrophage function.<ref name="pmid20338813">{{cite journal |vauthors=Carey B, Trapnell BC |title=The molecular basis of pulmonary alveolar proteinosis |journal=Clin. Immunol. |volume=135 |issue=2 |pages=223–35 |date=May 2010 |pmid=20338813 |pmc=2866141 |doi=10.1016/j.clim.2010.02.017 |url=}}</ref>   
*Genes involved in the pathogenesis of pulmonary alveolar proteinosis include:  
*Genes involved in the pathogenesis of pulmonary alveolar proteinosis include:  
**Surfactant proteins B and C (SFTPB, SFTPC) , ATP-binding cassette, subfamily A (ABCA3) , SLC7A7, MARS (Methionyl-tRNA synthetasegene ) and GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB) genes mutation in production of surfactant     
**[[Surfactant]] proteins B and C (SFTPB, SFTPC), [[ATP-binding cassette family|ATP-binding cassette]], subfamily A ([[ABCA3]]), [[SLC7A7]], [[MARS (gene)|MARS]] (methionyl-tRNA synthetasegene ) and GM-CSF receptor alpha and beta genes (CSF2RA and CSF2RB) genes mutation in production of [[surfactant]].      


*On gross pathology after lung wasings, fluid with milky composition are characteristic finding of pulmonary alveolar proteinosis. <ref name="pmid9516877">{{cite journal |vauthors=Mikami T, Yamamoto Y, Yokoyama M, Okayasu I |title=Pulmonary alveolar proteinosis: diagnosis using routinely processed smears of bronchoalveolar lavage fluid |journal=J. Clin. Pathol. |volume=50 |issue=12 |pages=981–4 |date=December 1997 |pmid=9516877 |pmc=500376 |doi= |url=}}</ref>
*On [[gross pathology]] after lung washings, fluid with milky composition are characteristic finding of pulmonary alveolar proteinosis. <ref name="pmid9516877">{{cite journal |vauthors=Mikami T, Yamamoto Y, Yokoyama M, Okayasu I |title=Pulmonary alveolar proteinosis: diagnosis using routinely processed smears of bronchoalveolar lavage fluid |journal=J. Clin. Pathol. |volume=50 |issue=12 |pages=981–4 |date=December 1997 |pmid=9516877 |pmc=500376 |doi= |url=}}</ref>
*On microscopic histopathological analysis, terminal bronchioles and alveoli are filled with a lipoproteinaceous material that will be pink after periodic acid-Schiff (PAS) stain. Oil red-O positive, PAS-positive macrophages and cholesterol crystals are another characteristic findings of pulmonary alveolar proteinosis. Multilamellated structures in the alveoli can be seen in electron microscopy.<ref name="pmid11391819">{{cite journal |vauthors=Maygarden SJ, Iacocca MV, Funkhouser WK, Novotny DB |title=Pulmonary alveolar proteinosis: a spectrum of cytologic, histochemical, and ultrastructural findings in bronchoalveolar lavage fluid |journal=Diagn. Cytopathol. |volume=24 |issue=6 |pages=389–95 |date=June 2001 |pmid=11391819 |doi= |url=}}</ref>
*On microscopic histopathological analysis, [[terminal bronchioles]] and [[alveoli]] are filled with a lipoproteinaceous material that will be pink after [[Periodic acid-Schiff stain|periodic acid-Schiff (PAS) stain]]. Oil red-O positive, PAS-positive [[Macrophage|macrophages]] and [[cholesterol]] crystals are another characteristic findings of pulmonary alveolar proteinosis. Multilamellated structures in the alveoli can be seen in [[electron microscopy]].<ref name="pmid11391819">{{cite journal |vauthors=Maygarden SJ, Iacocca MV, Funkhouser WK, Novotny DB |title=Pulmonary alveolar proteinosis: a spectrum of cytologic, histochemical, and ultrastructural findings in bronchoalveolar lavage fluid |journal=Diagn. Cytopathol. |volume=24 |issue=6 |pages=389–95 |date=June 2001 |pmid=11391819 |doi= |url=}}</ref>
   
   
==Causes==
==Causes==
The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with:
The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with:
* Exposure to insecticides, titanium dioxide, indium-tin oxide and silica dust<ref name="pmid5775743" />
* Exposure to [[insecticides]], [[titanium dioxide]], indium-tin oxide and [[silica]] dust<ref name="pmid5775743" />
* Hematologic malignancies<ref name="pmid8118651" />
* Hematologic [[malignancies]]<ref name="pmid8118651" />
* HIV infection (AIDS)<ref name="pmid18551202">{{cite journal |vauthors=Juvet SC, Hwang D, Waddell TK, Downey GP |title=Rare lung disease II: pulmonary alveolar proteinosis |journal=Can. Respir. J. |volume=15 |issue=4 |pages=203–10 |date=2008 |pmid=18551202 |pmc=2677953 |doi= |url=}}</ref>
* [[HIV]] infection ([[AIDS]])<ref name="pmid18551202">{{cite journal |vauthors=Juvet SC, Hwang D, Waddell TK, Downey GP |title=Rare lung disease II: pulmonary alveolar proteinosis |journal=Can. Respir. J. |volume=15 |issue=4 |pages=203–10 |date=2008 |pmid=18551202 |pmc=2677953 |doi= |url=}}</ref>
* Leflunomide, case report<ref name="pmid16916345">{{cite journal |vauthors=Wardwell NR, Miller R, Ware LB |title=Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug |journal=Respirology |volume=11 |issue=5 |pages=663–5 |date=September 2006 |pmid=16916345 |doi=10.1111/j.1440-1843.2006.00905.x |url=}}</ref>
* [[Leflunomide]], case report<ref name="pmid16916345">{{cite journal |vauthors=Wardwell NR, Miller R, Ware LB |title=Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug |journal=Respirology |volume=11 |issue=5 |pages=663–5 |date=September 2006 |pmid=16916345 |doi=10.1111/j.1440-1843.2006.00905.x |url=}}</ref>
* Recessive ''CSF2RA'' mutations
* Recessive ''CSF2RA'' mutations
==Differentiating [disease name] from other Diseases==
==Differentiating pulmonary alveolar proteinosis from other Diseases==
*[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:
*Pulmonary alveolar proteinosis must be differentiated from other diseases that cause [[Ground glass opacification on CT|ground glass]] opacities in [[radiography]] such as:<ref name="pmid228911825">{{cite journal |vauthors=Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ |title=Pulmonary alveolar proteinosis |journal=Can. Respir. J. |volume=19 |issue=4 |pages=243–5 |date=2012 |pmid=22891182 |pmc=3411387 |doi= |url=}}</ref>
:*[Differential dx1]
:*[[Infection]] (''[[Pneumocystis jirovecii]] ''or ''[[Mycoplasma]]'')
:*[Differential dx2]
:*[[Acute interstitial pneumonia]]
:*[Differential dx3]
:*[[Cardiogenic pulmonary edema]]
:*Noncardiogenic [[pulmonary edema]]
:*[[Lipoid pneumonia]]
:*Drug-related [[hypersensitivity reactions]]
   
   
==Epidemiology and Demographics==
==Epidemiology and Demographics==
* The prevalence of pulmonary alveolar proteinosis is approximately 1 per 100,000 individuals worldwide.
* The [[prevalence]] of pulmonary alveolar proteinosis is approximately 1 per 100,000 individuals worldwide.
* The incidence of pulmonary alveolar proteinosis is estimated to be 0.33 cases per 100,000 individuals in united states. <ref name="pmid21158654">{{cite journal |vauthors=Hunt S, Miller AL, Schissel S, Ross JJ |title=A crazy cause of dyspnea |journal=N. Engl. J. Med. |volume=363 |issue=25 |pages=e38 |date=December 2010 |pmid=21158654 |doi=10.1056/NEJMimc1008281 |url=}}</ref>
* The [[incidence]] of pulmonary alveolar proteinosis is estimated to be 0.33 cases per 100,000 individuals in united states. <ref name="pmid21158654">{{cite journal |vauthors=Hunt S, Miller AL, Schissel S, Ross JJ |title=A crazy cause of dyspnea |journal=N. Engl. J. Med. |volume=363 |issue=25 |pages=e38 |date=December 2010 |pmid=21158654 |doi=10.1056/NEJMimc1008281 |url=}}</ref>
   
   
===Age===
===Age===
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==Risk Factors==
==Risk Factors==
*Common risk factors in the development of pulmonary alveolar proteinosis are  
*Common risk factors in the development of pulmonary alveolar proteinosis are:
**Current or former cigarette smokers<ref name="pmid275145902">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>  
**Current or former cigarette smokers<ref name="pmid275145902">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>  
** HIV infection<ref name="pmid18551202" />  
** [[Human Immunodeficiency Virus (HIV)|HIV]] infection<ref name="pmid18551202" />  
   
   
== Natural History, Complications and Prognosis==
== Natural History, Complications and Prognosis==
*If left untreated, patients with pulmonary alveolar proteinosis may progress to develop pulmonary fibrosis, cor pulmonale. The natural history of secondary pulmonary alveolar proteinosis is related to underlying etiologies
*If left untreated, patients with pulmonary alveolar proteinosis may progress to develop [[pulmonary fibrosis]], [[cor pulmonale]]. The natural history of secondary pulmonary alveolar proteinosis is related to underlying etiologies.
*Common complications of pulmonary alveolar proteinosis include lung infections with Pneumocystis carinii, Mycobacterium avium-intracellulare , N asteroides ,  <ref name="pmid15497254">{{cite journal |vauthors=Abdul Rahman JA, Moodley YP, Phillips MJ |title=Pulmonary alveolar proteinosis associated with psoriasis and complicated by mycobacterial infection: successful treatment with granulocyte-macrophage colony stimulating factor after a partial response to whole lung lavage |journal=Respirology |volume=9 |issue=3 |pages=419–22 |date=August 2004 |pmid=15497254 |doi= |url=}}</ref>
*Common complications of pulmonary alveolar proteinosis include lung infections with [[Pneumocystis carinii]], [[Mycobacterium avium-intracellulare]], Nocardia asteroides. <ref name="pmid15497254">{{cite journal |vauthors=Abdul Rahman JA, Moodley YP, Phillips MJ |title=Pulmonary alveolar proteinosis associated with psoriasis and complicated by mycobacterial infection: successful treatment with granulocyte-macrophage colony stimulating factor after a partial response to whole lung lavage |journal=Respirology |volume=9 |issue=3 |pages=419–22 |date=August 2004 |pmid=15497254 |doi= |url=}}</ref>


*Prognosis is generally good for primary pulmonary alveolar proteinosis with whole lung lavage. Congenital pulmonary alveolar proteinosis respond well to lung transplantation. Prognosis for secondary pulmonary alveolar proteinosis is related to underlying etiologies.  
*Prognosis is generally good for primary pulmonary alveolar proteinosis with whole lung lavage. [[Congenital]] pulmonary alveolar proteinosis respond well to [[lung transplantation]]. Prognosis for secondary pulmonary alveolar proteinosis is related to underlying etiologies.  


== Diagnosis ==
== Diagnosis ==
===Diagnostic Criteria===
*The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:
:*[criterion 1]
:*[criterion 2]
:*[criterion 3]
:*[criterion 4]
=== Symptoms ===
=== Symptoms ===
*One third of patients are usually asymptomatic.<ref name="pmid182023482">{{cite journal |vauthors=Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K |title=Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan |journal=Am. J. Respir. Crit. Care Med. |volume=177 |issue=7 |pages=752–62 |date=April 2008 |pmid=18202348 |pmc=2720118 |doi=10.1164/rccm.200708-1271OC |url=}}</ref>
*One third of patients are usually [[asymptomatic]].<ref name="pmid182023482">{{cite journal |vauthors=Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K |title=Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan |journal=Am. J. Respir. Crit. Care Med. |volume=177 |issue=7 |pages=752–62 |date=April 2008 |pmid=18202348 |pmc=2720118 |doi=10.1164/rccm.200708-1271OC |url=}}</ref>
*Symptoms of pulmonary alveolar proteinosis may include the following:<ref name="pmid275145903">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
*Symptoms of pulmonary alveolar proteinosis may include the following:<ref name="pmid275145903">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
:*Dyspnea on exertion
:*[[Dyspnea]] on exertion
:*Cough ( productive or nonproduvtive)
:*[[Cough]] ([[Productive cough|productive]] or nonproduvtive)
:*Sputum
 
:*Fatigue
:*[[Fatigue]]
:*Weight loss  
:*[[Weight loss]]
:*Low-grade fever  
:*[[Low-grade fever]]
   
   
=== Physical Examination ===
=== Physical Examination ===
*  The physical examination is often normal. <ref name="pmid275145904">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
* The physical examination is often normal. <ref name="pmid275145904">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>


*Patients with [disease name] usually appear [general appearance].
*Physical examination may be remarkable for:<ref name="pmid9824014">{{cite journal |vauthors=Goldstein LS, Kavuru MS, Curtis-McCarthy P, Christie HA, Farver C, Stoller JK |title=Pulmonary alveolar proteinosis: clinical features and outcomes |journal=Chest |volume=114 |issue=5 |pages=1357–62 |date=November 1998 |pmid=9824014 |doi= |url=}}</ref><ref name="pmid182023483">{{cite journal |vauthors=Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K |title=Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan |journal=Am. J. Respir. Crit. Care Med. |volume=177 |issue=7 |pages=752–62 |date=April 2008 |pmid=18202348 |pmc=2720118 |doi=10.1164/rccm.200708-1271OC |url=}}</ref>
*Physical examination may be remarkable for:
:*[[Crackles]], but may be absent in pulmonary alveolar proteinosis with completely fluid-filled distal [[alveoli]]
:*Crackles, but may be absent in pulmonary alveolar proteinosis with completely fluid-filled distal alveoli.<ref name="pmid9824014">{{cite journal |vauthors=Goldstein LS, Kavuru MS, Curtis-McCarthy P, Christie HA, Farver C, Stoller JK |title=Pulmonary alveolar proteinosis: clinical features and outcomes |journal=Chest |volume=114 |issue=5 |pages=1357–62 |date=November 1998 |pmid=9824014 |doi= |url=}}</ref>
:*[[Clubbing]]
:*Clubbing<ref name="pmid182023483">{{cite journal |vauthors=Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K |title=Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan |journal=Am. J. Respir. Crit. Care Med. |volume=177 |issue=7 |pages=752–62 |date=April 2008 |pmid=18202348 |pmc=2720118 |doi=10.1164/rccm.200708-1271OC |url=}}</ref>
:*[[Cyanosis]]
:*Cyanosis
   
   
=== Laboratory Findings ===
=== Laboratory Findings ===
* Serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in autoimmune pulmonary alveolar proteinosis<ref name="pmid275145905">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
* Serum anti-granulocyte-macrophage colony-stimulating factor ([[GM-CSF]]) antibodies in [[autoimmune]] pulmonary alveolar proteinosis.<ref name="pmid275145905">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
* Complete blood count and differential in secondary pulmonary alveolar proteinosis due to hematologic malignancy.
* [[Complete blood count]] and differential in secondary pulmonary alveolar proteinosis due to [[hematologic malignancy]].
* Elevated serum level of GM-CSF in hereditary pulmonary alveolar proteinosis  
* Elevated serum level of [[GM-CSF]] in [[hereditary]] pulmonary alveolar proteinosis.<ref name="pmid275145906">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
* Secondary PAP – A complete blood count and differential is obtained to evaluate for hematologic malignancy or myelodysplastic syndrome. Testing for a GATA2 genetic variant may be appropriate in patients with the combination of familial myelodysplastic syndrome and PAP. (See 'Macrophage dysfunction' above.)
* Nonspecific laboratory findings:<ref name="pmid666104">{{cite journal |vauthors=Martin RJ, Rogers RM, Myers NM |title=PUlmonary alveolar proteinosis: shunt fraction and lactic acid dehydrogenase concentration as aids to diagnosis |journal=Am. Rev. Respir. Dis. |volume=117 |issue=6 |pages=1059–62 |date=June 1978 |pmid=666104 |doi=10.1164/arrd.1978.117.6.1059 |url=}}</ref>
** [[Hypergammaglobulinemia]]
** [[Polycythemia]]
** Increased [[lactate dehydrogenase]] (LDH) levels
** Elevated levels of lung [[surfactant]] proteins A and D (SP-A and SP-D)
** Elevated levels of [[Tumor marker|tumor markers]] ([[carcinoembryonic antigen]] [CEA], sialyl SSEA-1 [SLX], carbohydrate antigens sialyl Lewis-a [CA 19-9]) <ref name="pmid275145909">{{cite journal |vauthors=Suzuki T, Trapnell BC |title=Pulmonary Alveolar Proteinosis Syndrome |journal=Clin. Chest Med. |volume=37 |issue=3 |pages=431–40 |date=September 2016 |pmid=27514590 |doi=10.1016/j.ccm.2016.04.006 |url=}}</ref>
===Imaging Findings===


*There are no specific laboratory findings associated with [disease name].
===== Chest X-ray: =====
* Bat wing distribution of [[bilateral]] symmetric alveolar opacities in mid and lower lung zones.<ref name="pmid22891182">{{cite journal |vauthors=Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ |title=Pulmonary alveolar proteinosis |journal=Can. Respir. J. |volume=19 |issue=4 |pages=243–5 |date=2012 |pmid=22891182 |pmc=3411387 |doi= |url=}}</ref>
* Segmental [[atelectasis]] due to bronchiolar [[obstruction]].<ref name="pmid3553760">{{cite journal |vauthors=Prakash UB, Barham SS, Carpenter HA, Dines DE, Marsh HM |title=Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review |journal=Mayo Clin. Proc. |volume=62 |issue=6 |pages=499–518 |date=June 1987 |pmid=3553760 |doi= |url=}}</ref>
* In chronic cases, focal [[fibrosis]] may be seen.<ref name="pmid4832278">{{cite journal |vauthors=Hudson AR, Halprin GM, Miller JA, Kilburn KH |title=Pulmonary interstitial fibrosis following alveolar proteinosis |journal=Chest |volume=65 |issue=6 |pages=700–2 |date=June 1974 |pmid=4832278 |doi= |url=}}</ref>


*A  [positive/negative] [test name] is diagnostic of [disease name].
===== High resolution computed tomography (HRCT): =====
*An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
* Ground-glass opacification with crazy-paving pattern (interlobular septal thickening).<ref name="pmid228911822">{{cite journal |vauthors=Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ |title=Pulmonary alveolar proteinosis |journal=Can. Respir. J. |volume=19 |issue=4 |pages=243–5 |date=2012 |pmid=22891182 |pmc=3411387 |doi= |url=}}</ref><ref name="pmid3186983">{{cite journal |vauthors=Godwin JD, Müller NL, Takasugi JE |title=Pulmonary alveolar proteinosis: CT findings |journal=Radiology |volume=169 |issue=3 |pages=609–13 |date=December 1988 |pmid=3186983 |doi=10.1148/radiology.169.3.3186983 |url=}}</ref>  
*Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].
===Imaging Findings===
*There are no [imaging study] findings associated with [disease name].
*[Imaging study 1] is the imaging modality of choice for [disease name].
*On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
*[Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].
   
=== Other Diagnostic Studies ===
=== Other Diagnostic Studies ===
*[Disease name] may also be diagnosed using [diagnostic study name].
 
*Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].
====== Pulmonary function test: ======
* Reduction in the diffusing capacity for carbon monoxide ([[DLCO]]).<ref name="pmid182023484">{{cite journal |vauthors=Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K |title=Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan |journal=Am. J. Respir. Crit. Care Med. |volume=177 |issue=7 |pages=752–62 |date=April 2008 |pmid=18202348 |pmc=2720118 |doi=10.1164/rccm.200708-1271OC |url=}}</ref>
* Maybe decrease in [[forced vital capacity]].<ref name="pmid12119235">{{cite journal |vauthors=Seymour JF, Presneill JJ |title=Pulmonary alveolar proteinosis: progress in the first 44 years |journal=Am. J. Respir. Crit. Care Med. |volume=166 |issue=2 |pages=215–35 |date=July 2002 |pmid=12119235 |doi=10.1164/rccm.2109105 |url=}}</ref>
 
====== Bronchoalveolar lavage (BAL): ======
* It is done via flexible [[bronchoscopy]].
* Milky or opaque appearance because of abundant lipoproteinaceous material.<ref name="pmid21900000">{{cite journal |vauthors=Bonella F, Bauer PC, Griese M, Ohshimo S, Guzman J, Costabel U |title=Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients |journal=Respir Med |volume=105 |issue=12 |pages=1908–16 |date=December 2011 |pmid=21900000 |doi=10.1016/j.rmed.2011.08.018 |url=}}</ref>
 
====== Surgical lung biopsy: ======
*It is done via video-assisted thoracoscopic [[biopsy]].<ref name="pmid182023485">{{cite journal |vauthors=Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K |title=Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan |journal=Am. J. Respir. Crit. Care Med. |volume=177 |issue=7 |pages=752–62 |date=April 2008 |pmid=18202348 |pmc=2720118 |doi=10.1164/rccm.200708-1271OC |url=}}</ref>
   
   
== Treatment ==
== Treatment ==
=== Medical Therapy ===
 
*There is no treatment for [disease name]; the mainstay of therapy is supportive care.
=== Interventional therapy ===
* Whole-lung lavage (WLL) with normal saline under general [[anesthesia]]: <ref name="pmid26481735">{{cite journal |vauthors=Zhao YY, Huang H, Liu YZ, Song XY, Li S, Xu ZJ |title=Whole Lung Lavage Treatment of Chinese Patients with Autoimmune Pulmonary Alveolar Proteinosis: A Retrospective Long-term Follow-up Study |journal=Chin. Med. J. |volume=128 |issue=20 |pages=2714–9 |date=October 2015 |pmid=26481735 |pmc=4736873 |doi=10.4103/0366-6999.167295 |url=}}</ref>
*The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
** Indication:<ref name="CampoLuisetti2016">{{cite journal|last1=Campo|first1=Ilaria|last2=Luisetti|first2=Maurizio|last3=Griese|first3=Matthias|last4=Trapnell|first4=Bruce C.|last5=Bonella|first5=Francesco|last6=Grutters|first6=Jan|last7=Nakata|first7=Koh|last8=Van Moorsel|first8=Coline H. M.|last9=Costabel|first9=Ulrich|last10=Cottin|first10=Vincent|last11=Ichiwata|first11=Toshio|last12=Inoue|first12=Yoshikazu|last13=Braschi|first13=Antonio|last14=Bonizzoni|first14=Giacomo|last15=Iotti|first15=Giorgio A.|last16=Tinelli|first16=Carmine|last17=Rodi|first17=Giuseppe|title=Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures|journal=Orphanet Journal of Rare Diseases|volume=11|issue=1|year=2016|issn=1750-1172|doi=10.1186/s13023-016-0497-9}}</ref>
*[Medical therapy 1] acts by [mechanism of action 1].
*** Resting PaO2 <65 mmHg
*Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].
*** Alveolar-arterial O2 gradient ≥40 mmHg at rest
*** Severe [[dyspnea]]
*** [[Hypoxemia]] 
** Contraindication:<ref name="MichaudReddy2009">{{cite journal|last1=Michaud|first1=Gaëtane|last2=Reddy|first2=Chakravarthy|last3=Ernst|first3=Armin|title=Whole-Lung Lavage for Pulmonary Alveolar Proteinosis|journal=Chest|volume=136|issue=6|year=2009|pages=1678–1681|issn=00123692|doi=10.1378/chest.09-2295}}</ref>
*** Clotting disorders
*** [[Anesthetic]] risks
*** Cardiopulmonary instability
 
=== Medical therapy ===
* Recombinant [[Granulocyte macrophage colony stimulating factor|GM-CSF]] ( sargramostim) by inhaled or subcutenous injections:<ref name="pmid10764303">{{cite journal |vauthors=Kavuru MS, Sullivan EJ, Piccin R, Thomassen MJ, Stoller JK |title=Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis |journal=Am. J. Respir. Crit. Care Med. |volume=161 |issue=4 Pt 1 |pages=1143–8 |date=April 2000 |pmid=10764303 |doi=10.1164/ajrccm.161.4.9906044 |url=}}</ref>
** For patients with failed whole-lung lavage (WLL)
 
* [[Rituximab]] ( anti-CD20 monoclonal antibody): for refractory [[autoimmune]] pulmonary alveolar proteinosis.<ref name="pmid19483052">{{cite journal |vauthors=Borie R, Debray MP, Laine C, Aubier M, Crestani B |title=Rituximab therapy in autoimmune pulmonary alveolar proteinosis |journal=Eur. Respir. J. |volume=33 |issue=6 |pages=1503–6 |date=June 2009 |pmid=19483052 |doi=10.1183/09031936.00160908 |url=}}</ref>
* Therapeutic plasma exchange: for patients with failed whole lung lavage.<ref name="pmid19407056">{{cite journal |vauthors=Luisetti M, Rodi G, Perotti C, Campo I, Mariani F, Pozzi E, Trapnell BC |title=Plasmapheresis for treatment of pulmonary alveolar proteinosis |journal=Eur. Respir. J. |volume=33 |issue=5 |pages=1220–2 |date=May 2009 |pmid=19407056 |doi=10.1183/09031936.00097508 |url=}}</ref>
 
=== Surgery ===
=== Surgery ===
*Surgery is the mainstay of therapy for [disease name].
* Lung [[transplantation]] in refractory cases especially for [[congenital]] pulmonary alveolar proteinosis.<ref name="pmid228911823">{{cite journal |vauthors=Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ |title=Pulmonary alveolar proteinosis |journal=Can. Respir. J. |volume=19 |issue=4 |pages=243–5 |date=2012 |pmid=22891182 |pmc=3411387 |doi= |url=}}</ref>
*[Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
 
*[Surgical procedure] can only be performed for patients with [disease stage] [disease name].
=== Prevention ===
=== Prevention ===
*There are no primary preventive measures available for [disease name].
*Avoiding further exposure is the effective measure for the secondary prevention of pulmonary alveolar proteinosis due to inorganic dust or [[insecticides]].<ref name="pmid228911824">{{cite journal |vauthors=Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ |title=Pulmonary alveolar proteinosis |journal=Can. Respir. J. |volume=19 |issue=4 |pages=243–5 |date=2012 |pmid=22891182 |pmc=3411387 |doi= |url=}}</ref> 
   
   
*Effective measures for the secondary prevention of pulmonary alveolar proteinosis due to inorganic dust or insecticides should avoid further exposure.  
*Annual [[influenza vaccination]] and age approriate [[pneumococcal pneumonia]] vaccination.  
*


*Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
   
   
[[Category:Pick One of 28 Approved]]
 


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[[Category:Medicine]]
 
[[Category:Pulmonology]]
==Overview==
[[Category:Up-To-Date]]
'''Pulmonary alveolar proteinosis''' -(PAP) is a rare [[lung]] [[disease]] in which abnormal accumulation of [[surfactant]] occurs within the [[alveoli]], interfering with [[gas exchange]].  PAP can occur in a primary form or secondarily in the settings of malignancy (especially in myeloid [[leukemia]]), pulmonary infection, or environmental exposure to dusts or chemicals.  Rare familial forms have also been recognized, suggesting a [[genetics|genetic]] component in some cases. <ref>Rosen SH, Castleman B, and Liebow AA. Pulmonary alveolar proteinosis. New England Journal of Medicine 1958; 258: 1123-1142.</ref> <ref>Seymour JF and Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. American Journal of Respiratory and Critical Care Medicine 2002; 166: 215-235.</ref> <ref>Shah PL, Hansell D, Lawson PR, et al. Pulmonary alveolar proteinosis; clinical aspects and current concepts on pathogenesis. Thorax 2000; 55: 67-77.</ref> <ref>Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc. Natl. Acad. Sci. USA 1994; 91: 5592-5596.</ref>
 
==Historical Perspective== 
 
==Pathophysiology==
Although the cause of PAP remains obscure, a major breakthrough in the understanding of the [[etiology]] of the disease came by the chance observation that mice bred for experimental study to lack a hematologic [[growth factor]] known as [[Granulocyte-colony stimulating factor|granulocyte-macrophage colony stimulating factor (GM-CSF)]] developed a pulmonary [[syndrome]] of abnormal surfactant accumulation resembling human PAP.  The implications of this finding are still being explored, but significant progress was reported in February, 2007.  Researchers in that report discussed the presence of anti-[[GM-CSF]] [[autoantibodies]] in patients with PAP, and duplicated that [[syndrome]] with the infusion of these [[autoantibodies]] into mice. <ref>{{cite journal |author=Uchida K, Beck D, Yamamoto T, Berclaz P, Abe S, Staudt M, Carey B, Filippi M, Wert S, Denson L, Puchalski J, Hauck D, Trapnell B |title=GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis |journal=N Engl J Med |volume=356 |issue=6 |pages=567-79 |year=2007 |pmid=17287477}}</ref>
 
==Causes==
Pulmonary alveolar proteinosis is an idiopathic disease, but studies have linked causes to production of antibodies that neutralize GM-CSF, [[granulocyte-macrophage colony-stimulating factor]]. Occasionally, development of pulmonary alveolar proteinosis is related to exposure of toxic substances, such as inorganic dusts, infection with [[Pneumocystis jirovecii]], certain cancers, and immunosuppressants. It rarely occurs in newborns.
 
There are several types of clinical forms of [[Pulmonary alveolar proteinosis]]; primary, secondary, and congenital. Primary PAP involves high levels of antibodies that neutralize GM-CSF, [[granulocyte-macrophage colony-stimulating factor]]. Secondary PAP occurs from clinical conditions that reduce the numbers and functions of alveolar macrophages. Congenital PAP is due to genetic mutations in the genes encoding surfactant proteins of the receptor for [[granulocyte-macrophage colony-stimulating factor]].<ref name="pmid14695413">{{cite journal| author=Trapnell BC, Whitsett JA, Nakata K| title=Pulmonary alveolar proteinosis. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 26 | pages= 2527-39 | pmid=14695413 | doi=10.1056/NEJMra023226 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14695413  }} </ref>
 
==Causes==
===Common Causes===
*[[Pneumocystis jirovecii]]
*[[Respiratory failure]]
*Uncontrolled infection
*Respiratory Pathogens
*Opportunistic Pathogens: [[Nocardia]]
*[[Sirolimus]]
*[[Prednisone]]
*Inorganic dusts
*Inhalation of [[silica]] dust
*Exposure to [[insecticides]]
*aluminum dust
*[[titanium dioxide]]
*[[Haematological]] malignancies
*[[HIV]] infection.
 
===Causes by Organ System===
{| style="width:80%; height:100px" border="1"
| style="width:25%" bgcolor="LightSteelBlue" ; border="1" | '''Cardiovascular'''
| style="width:75%" bgcolor="Beige" ; border="1" |No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Chemical / poisoning'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Dermatologic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Drug Side Effect'''
| bgcolor="Beige" |[[Sirolimus]], [[Prednisone]]
|-
|- bgcolor="LightSteelBlue"
| '''Ear Nose Throat'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Endocrine'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Environmental'''
| bgcolor="Beige" | Inorganic dusts, Inhalation of [[silica]] dust, Exposure to [[insecticides]], aluminum dust, [[titanium dioxide]]
|-
|- bgcolor="LightSteelBlue"
| '''Gastroenterologic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Genetic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Hematologic'''
| bgcolor="Beige" | [[Haematological]] malignancies
|-
|- bgcolor="LightSteelBlue"
| '''Iatrogenic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Infectious Disease'''
| bgcolor="Beige" | Uncontrolled infection, Respiratory Pathogens, [[Nocardia]], [[HIV]] infection
|-
|- bgcolor="LightSteelBlue"
| '''Musculoskeletal / Ortho'''
| bgcolor="Beige" | [No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Neurologic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Nutritional / Metabolic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Obstetric/Gynecologic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Oncologic'''
| bgcolor="Beige" | [[Haematological]] malignancies
|-
|- bgcolor="LightSteelBlue"
| '''Opthalmologic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Overdose / Toxicity'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Psychiatric'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Pulmonary'''
| bgcolor="Beige" |[[Pneumocystis jirovecii]], [[Respiratory failure]]
|-
|- bgcolor="LightSteelBlue"
| '''Renal / Electrolyte'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Rheum / Immune / Allergy'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Sexual'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Trauma'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Urologic'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Dental'''
| bgcolor="Beige" | No underlying causes
|-
|- bgcolor="LightSteelBlue"
| '''Miscellaneous'''
| bgcolor="Beige" | No underlying causes
|-
|}
 
===Causes in Alphabetical Order===
 
{{col-begin|width=80%}}
{{col-break|width=33%}}
 
*Aluminum dust
*[[Haematological]] malignancies
*[[HIV]] infection
 
*Inorganic Dusts
*[[Insecticides]]
*Opportunistic Pathogens: [[Nocardia]]
*[[Pneumocystis jirovecii]]
*[[Prednisone]]
 
*[[Respiratory failure]]
*Respiratory Pathogens
*[[Silica]] dust
*[[Sirolimus]]
*[[Titanium dioxide]]
*Uncontrolled infection
 
{{col-end}}
 
==Natural History==
The clinical course of PAP is unpredictable. Spontaneous remission is recognized; some patients have stable symptoms.
==Complications==
Death may occur due to progression of PAP or due to the underlying disease associated with PAP. Individuals with PAP are more vulnerable to [[pneumonia|infection of the lung]] by [[bacterium|bacteria]] or [[fungi]].
==Prognosis==
 
==History and Symptoms==
The [[symptoms]] of PAP include:
*[[Dyspnea]]<ref name="pmid14695413">{{cite journal| author=Trapnell BC, Whitsett JA, Nakata K| title=Pulmonary alveolar proteinosis. | journal=N Engl J Med | year= 2003 | volume= 349 | issue= 26 | pages= 2527-39 | pmid=14695413 | doi=10.1056/NEJMra023226 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14695413  }} </ref>
*[[Cough]]
*[[Sputum]]
*[[Fatigue]]
*[[Fever]]
*[[Anorexia]]
*[[Hemoptysis]]
*[[Crackles]]
*[[Cyanosis]]
*[[Clubbing]]
 
==Chest X Ray==
Classic radiographic finding is bilateral, symmetric [[alveolar]] [[consolidation]] or ground-glass opacity, particularly in a [[perihilar]] or [[hilar]] distribution resembling [[pulmonary edema]].
 
==CT==
* CT typically shows diffuse ground-glass attenuation with superimposed crazy-paving pattern (intra- and interlobular septal thickening, often in polygonal shapes representing the secondary pulmonary lobule).
'''Patient#1'''
<gallery>
Image:
Pulmonary-alveolar-proteinosis-001.jpg
Image:
Pulmonary-alveolar-proteinosis-002.jpg</gallery>
'''Patient #1: Proven PAP but not quite the classic crazy-paving pattern'''
<gallery>
Image:
Pulmonary alveolar proteinosis 201.jpg
Image:
Pulmonary alveolar proteinosis 202.jpg
Image:
Pulmonary alveolar proteinosis 203.jpg
Image:
Pulmonary alveolar proteinosis 204.jpg
</gallery>
 
==Other Diagnostic Studies==
[[Diagnosis]] is generally made by surgical or endoscopic [[biopsy]] of the lung, revealing the distinctive pathologic finding.
=== Histopathological Findings: Pulmonary alveolar proteinosis===
 
{{#ev:youtube|L9fVRzcPkEQ}}
 
==Medical Therapy==
The use of [[GM-CSF]] injections has also been attempted, with variable success.
 
==Surgery==
The standard treatment for PAP is whole-lung [[lavage]], in which sterile fluid is instilled into the lung and then removed, along with the abnormal [[surfactant]] material.  This is generally effective at ameliorating symptoms, often for prolonged periods. Lung [[transplantation]] can be performed in refractory cases.
 
==References==
{{reflist|2}}

Latest revision as of 23:53, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mahda Alihashemi M.D. [2] [3] [4]

Synonyms and keywords:Pulmonary alveolar phospholipoproteinosis

Overview

Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958. Pulmonary alveolar proteinosis ( PAP) may be classified into 2 subtypes, primary and secondary pulmonary alveolar proteinosis. The pathogenesis of pulmonary alveolar proteinosis is characterized by the intraalveolar accumulation of surfactant phospholipid and apoproteins. Pulmonary alveolar proteinosis develop because of reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) levels or function and/or impaired alveolar macrophage function. On gross pathology after lung washings, fluid with the milky composition are the characteristic finding of pulmonary alveolar proteinosis. On microscopic histopathological analysis, terminal bronchioles and alveoli are filled with a lipoproteinaceous material that will be pink after periodic acid-Schiff (PAS) stain. The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with exposure to insecticides, hematologic malignancies, or HIV infection. Pulmonary alveolar proteinosis must be differentiated from other diseases that cause ground glass opacities in radiography. Pulmonary alveolar proteinosis is more commonly observed among patients aged 40- 50 years old. Men are more commonly affected with pulmonary alveolar proteinosis than women. Common risk factors in the development of pulmonary alveolar proteinosis are current or former cigarette smokers and HIV infection. If left untreated, patients with pulmonary alveolar proteinosis may progress to develop pulmonary fibrosis, cor pulmonale. Symptoms of pulmonary alveolar proteinosis may include dyspnea on exertion, cough. The physical examination is often normal. Laboratory findings are serum anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in autoimmune pulmonary alveolar proteinosis and elevated serum level of GM-CSF in hereditary pulmonary alveolar proteinosis. Imaging studies include chest x-ray and high resolution computed tomography (HRCT). Treatment include whole-lung lavage (WLL), recombinant GM-CSF and lung transplantation.

Historical Perspective

  • Pulmonary alveolar proteinosis ( PAP) was first discovered by Samuel Rosen, Benjamin Castleman, and Averill Liebow, in 1958, during pathologic investigations of material filling the alveoli. [1]
  • In 1960, the first therapeutic bronchoalveolar lavage by repeated segmental flooding was developed by Dr. Jose Ramirez-Rivera to treat pulmonary alveolar proteinosis. [2]

Classification

Pulmonary alveolar proteinosis ( PAP) may be classified into 2 subtypes:

Primary Pulmonary alveolar proteinosis:
Secondary pulmonary alveolar proteinosis:

Pathophysiology

Causes

The exact etiology of pulmonary alveolar proteinosis (PAP) is unknown, but it may be associated with:

Differentiating pulmonary alveolar proteinosis from other Diseases

  • Pulmonary alveolar proteinosis must be differentiated from other diseases that cause ground glass opacities in radiography such as:[17]

Epidemiology and Demographics

  • The prevalence of pulmonary alveolar proteinosis is approximately 1 per 100,000 individuals worldwide.
  • The incidence of pulmonary alveolar proteinosis is estimated to be 0.33 cases per 100,000 individuals in united states. [18]

Age

  • Pulmonary alveolar proteinosis is more commonly observed among patients aged 40- 50 years old.[19]

Gender

  • Men are more commonly affected with pulmonary alveolar proteinosis than women. The men to women ratio is approximately 2 to 1.

Race

  • There is no racial predilection for pulmonary alveolar protoeinosis.

Risk Factors

  • Common risk factors in the development of pulmonary alveolar proteinosis are:
    • Current or former cigarette smokers[20]
    • HIV infection[15]

Natural History, Complications and Prognosis

  • Prognosis is generally good for primary pulmonary alveolar proteinosis with whole lung lavage. Congenital pulmonary alveolar proteinosis respond well to lung transplantation. Prognosis for secondary pulmonary alveolar proteinosis is related to underlying etiologies.

Diagnosis

Symptoms

  • One third of patients are usually asymptomatic.[22]
  • Symptoms of pulmonary alveolar proteinosis may include the following:[23]

Physical Examination

  • The physical examination is often normal. [24]
  • Physical examination may be remarkable for:[25][26]

Laboratory Findings

Imaging Findings

Chest X-ray:
High resolution computed tomography (HRCT):
  • Ground-glass opacification with crazy-paving pattern (interlobular septal thickening).[34][35]

Other Diagnostic Studies

Pulmonary function test:
 Bronchoalveolar lavage (BAL):
  • It is done via flexible bronchoscopy.
  • Milky or opaque appearance because of abundant lipoproteinaceous material.[38]
Surgical lung biopsy:
  • It is done via video-assisted thoracoscopic biopsy.[39]

Treatment

Interventional therapy

  • Whole-lung lavage (WLL) with normal saline under general anesthesia: [40]
    • Indication:[41]
      • Resting PaO2 <65 mmHg
      • Alveolar-arterial O2 gradient ≥40 mmHg at rest
      • Severe dyspnea
      • Hypoxemia 
    • Contraindication:[42]
      • Clotting disorders
      • Anesthetic risks
      • Cardiopulmonary instability

Medical therapy

  • Recombinant GM-CSF ( sargramostim) by inhaled or subcutenous injections:[43]
    • For patients with failed whole-lung lavage (WLL)
  • Rituximab ( anti-CD20 monoclonal antibody): for refractory autoimmune pulmonary alveolar proteinosis.[44]
  • Therapeutic plasma exchange: for patients with failed whole lung lavage.[45]

Surgery

Prevention

  • Avoiding further exposure is the effective measure for the secondary prevention of pulmonary alveolar proteinosis due to inorganic dust or insecticides.[47]

References

  1. ↑ Rosen, Samuel H.; Castleman, Benjamin; Liebow, Averill A.; Enzinger, Frank M.; Hunt, Richard T. N. (1958). "Pulmonary Alveolar Proteinosis". New England Journal of Medicine. 258 (23): 1123–1142. doi:10.1056/NEJM195806052582301. ISSN 0028-4793.
  2. ↑ Ramirez-R., Jose; Nyka, Walenty; McLaughlin, Joseph (1963). "Pulmonary Alveolar Proteinosis". New England Journal of Medicine. 268 (4): 165–171. doi:10.1056/NEJM196301242680401. ISSN 0028-4793.
  3. ↑ Suzuki T, Trapnell BC (September 2016). "Pulmonary Alveolar Proteinosis Syndrome". Clin. Chest Med. 37 (3): 431–40. doi:10.1016/j.ccm.2016.04.006. PMID 27514590.
  4. ↑ Brasch F, Birzele J, Ochs M, Guttentag SH, Schoch OD, Boehler A, Beers MF, Müller KM, Hawgood S, Johnen G (September 2004). "Surfactant proteins in pulmonary alveolar proteinosis in adults". Eur. Respir. J. 24 (3): 426–35. doi:10.1183/09031936.04.00076403. PMID 15358702.
  5. ↑ Mulugeta S, Gray JM, Notarfrancesco KL, Gonzales LW, Koval M, Feinstein SI, Ballard PL, Fisher AB, Shuman H (June 2002). "Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3". J. Biol. Chem. 277 (25): 22147–55. doi:10.1074/jbc.M201812200. PMID 11940594.
  6. ↑ Salerno T, Peca D, Menchini L, Schiavino A, Petreschi F, Occasi F, Cogo P, Danhaive O, Cutrera R (March 2014). "Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene". Pediatr. Pulmonol. 49 (3): E42–4. doi:10.1002/ppul.22788. PMID 23997037.
  7. ↑ "GeneReviews® - NCBI Bookshelf".
  8. ↑ Hadchouel A, Wieland T, Griese M, Baruffini E, Lorenz-Depiereux B, Enaud L, Graf E, Dubus JC, Halioui-Louhaichi S, Coulomb A, Delacourt C, Eckstein G, Zarbock R, Schwarzmayr T, Cartault F, Meitinger T, Lodi T, de Blic J, Strom TM (May 2015). "Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on Réunion Island". Am. J. Hum. Genet. 96 (5): 826–31. doi:10.1016/j.ajhg.2015.03.010. PMC 4570277. PMID 25913036.
  9. ↑ 9.0 9.1 Buechner HA, Ansari A (April 1969). "Acute silico-proteinosis. A new pathologic variant of acute silicosis in sandblasters, characterized by histologic features resembling alveolar proteinosis". Dis Chest. 55 (4): 274–8. PMID 5775743.
  10. ↑ 10.0 10.1 Cordonnier C, Fleury-Feith J, Escudier E, Atassi K, Bernaudin JF (March 1994). "Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients". Am. J. Respir. Crit. Care Med. 149 (3 Pt 1): 788–94. doi:10.1164/ajrccm.149.3.8118651. PMID 8118651.
  11. ↑ Sharma S, Nadrous HF, Peters SG, Tefferi A, Litzow MR, Aubry MC, Afessa B (September 2005). "Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings". Chest. 128 (3): 1385–92. doi:10.1378/chest.128.3.1385. PMID 16162733.
  12. ↑ Carey B, Trapnell BC (May 2010). "The molecular basis of pulmonary alveolar proteinosis". Clin. Immunol. 135 (2): 223–35. doi:10.1016/j.clim.2010.02.017. PMC 2866141. PMID 20338813.
  13. ↑ Mikami T, Yamamoto Y, Yokoyama M, Okayasu I (December 1997). "Pulmonary alveolar proteinosis: diagnosis using routinely processed smears of bronchoalveolar lavage fluid". J. Clin. Pathol. 50 (12): 981–4. PMC 500376. PMID 9516877.
  14. ↑ Maygarden SJ, Iacocca MV, Funkhouser WK, Novotny DB (June 2001). "Pulmonary alveolar proteinosis: a spectrum of cytologic, histochemical, and ultrastructural findings in bronchoalveolar lavage fluid". Diagn. Cytopathol. 24 (6): 389–95. PMID 11391819.
  15. ↑ 15.0 15.1 Juvet SC, Hwang D, Waddell TK, Downey GP (2008). "Rare lung disease II: pulmonary alveolar proteinosis". Can. Respir. J. 15 (4): 203–10. PMC 2677953. PMID 18551202.
  16. ↑ Wardwell NR, Miller R, Ware LB (September 2006). "Pulmonary alveolar proteinosis associated with a disease-modifying antirheumatoid arthritis drug". Respirology. 11 (5): 663–5. doi:10.1111/j.1440-1843.2006.00905.x. PMID 16916345.
  17. ↑ Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ (2012). "Pulmonary alveolar proteinosis". Can. Respir. J. 19 (4): 243–5. PMC 3411387. PMID 22891182.
  18. ↑ Hunt S, Miller AL, Schissel S, Ross JJ (December 2010). "A crazy cause of dyspnea". N. Engl. J. Med. 363 (25): e38. doi:10.1056/NEJMimc1008281. PMID 21158654.
  19. ↑ Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K (April 2008). "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan". Am. J. Respir. Crit. Care Med. 177 (7): 752–62. doi:10.1164/rccm.200708-1271OC. PMC 2720118. PMID 18202348.
  20. ↑ Suzuki T, Trapnell BC (September 2016). "Pulmonary Alveolar Proteinosis Syndrome". Clin. Chest Med. 37 (3): 431–40. doi:10.1016/j.ccm.2016.04.006. PMID 27514590.
  21. ↑ Abdul Rahman JA, Moodley YP, Phillips MJ (August 2004). "Pulmonary alveolar proteinosis associated with psoriasis and complicated by mycobacterial infection: successful treatment with granulocyte-macrophage colony stimulating factor after a partial response to whole lung lavage". Respirology. 9 (3): 419–22. PMID 15497254.
  22. ↑ Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K (April 2008). "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan". Am. J. Respir. Crit. Care Med. 177 (7): 752–62. doi:10.1164/rccm.200708-1271OC. PMC 2720118. PMID 18202348.
  23. ↑ Suzuki T, Trapnell BC (September 2016). "Pulmonary Alveolar Proteinosis Syndrome". Clin. Chest Med. 37 (3): 431–40. doi:10.1016/j.ccm.2016.04.006. PMID 27514590.
  24. ↑ Suzuki T, Trapnell BC (September 2016). "Pulmonary Alveolar Proteinosis Syndrome". Clin. Chest Med. 37 (3): 431–40. doi:10.1016/j.ccm.2016.04.006. PMID 27514590.
  25. ↑ Goldstein LS, Kavuru MS, Curtis-McCarthy P, Christie HA, Farver C, Stoller JK (November 1998). "Pulmonary alveolar proteinosis: clinical features and outcomes". Chest. 114 (5): 1357–62. PMID 9824014.
  26. ↑ Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K (April 2008). "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan". Am. J. Respir. Crit. Care Med. 177 (7): 752–62. doi:10.1164/rccm.200708-1271OC. PMC 2720118. PMID 18202348.
  27. ↑ Suzuki T, Trapnell BC (September 2016). "Pulmonary Alveolar Proteinosis Syndrome". Clin. Chest Med. 37 (3): 431–40. doi:10.1016/j.ccm.2016.04.006. PMID 27514590.
  28. ↑ Suzuki T, Trapnell BC (September 2016). "Pulmonary Alveolar Proteinosis Syndrome". Clin. Chest Med. 37 (3): 431–40. doi:10.1016/j.ccm.2016.04.006. PMID 27514590.
  29. ↑ Martin RJ, Rogers RM, Myers NM (June 1978). "PUlmonary alveolar proteinosis: shunt fraction and lactic acid dehydrogenase concentration as aids to diagnosis". Am. Rev. Respir. Dis. 117 (6): 1059–62. doi:10.1164/arrd.1978.117.6.1059. PMID 666104.
  30. ↑ Suzuki T, Trapnell BC (September 2016). "Pulmonary Alveolar Proteinosis Syndrome". Clin. Chest Med. 37 (3): 431–40. doi:10.1016/j.ccm.2016.04.006. PMID 27514590.
  31. ↑ Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ (2012). "Pulmonary alveolar proteinosis". Can. Respir. J. 19 (4): 243–5. PMC 3411387. PMID 22891182.
  32. ↑ Prakash UB, Barham SS, Carpenter HA, Dines DE, Marsh HM (June 1987). "Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review". Mayo Clin. Proc. 62 (6): 499–518. PMID 3553760.
  33. ↑ Hudson AR, Halprin GM, Miller JA, Kilburn KH (June 1974). "Pulmonary interstitial fibrosis following alveolar proteinosis". Chest. 65 (6): 700–2. PMID 4832278.
  34. ↑ Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ (2012). "Pulmonary alveolar proteinosis". Can. Respir. J. 19 (4): 243–5. PMC 3411387. PMID 22891182.
  35. ↑ Godwin JD, Müller NL, Takasugi JE (December 1988). "Pulmonary alveolar proteinosis: CT findings". Radiology. 169 (3): 609–13. doi:10.1148/radiology.169.3.3186983. PMID 3186983.
  36. ↑ Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K (April 2008). "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan". Am. J. Respir. Crit. Care Med. 177 (7): 752–62. doi:10.1164/rccm.200708-1271OC. PMC 2720118. PMID 18202348.
  37. ↑ Seymour JF, Presneill JJ (July 2002). "Pulmonary alveolar proteinosis: progress in the first 44 years". Am. J. Respir. Crit. Care Med. 166 (2): 215–35. doi:10.1164/rccm.2109105. PMID 12119235.
  38. ↑ Bonella F, Bauer PC, Griese M, Ohshimo S, Guzman J, Costabel U (December 2011). "Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients". Respir Med. 105 (12): 1908–16. doi:10.1016/j.rmed.2011.08.018. PMID 21900000.
  39. ↑ Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, Kasahara Y, Tatsumi K, Hojo M, Ichiwata T, Tanaka N, Yamaguchi E, Eda R, Oishi K, Tsuchihashi Y, Kaneko C, Nukiwa T, Sakatani M, Krischer JP, Nakata K (April 2008). "Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan". Am. J. Respir. Crit. Care Med. 177 (7): 752–62. doi:10.1164/rccm.200708-1271OC. PMC 2720118. PMID 18202348.
  40. ↑ Zhao YY, Huang H, Liu YZ, Song XY, Li S, Xu ZJ (October 2015). "Whole Lung Lavage Treatment of Chinese Patients with Autoimmune Pulmonary Alveolar Proteinosis: A Retrospective Long-term Follow-up Study". Chin. Med. J. 128 (20): 2714–9. doi:10.4103/0366-6999.167295. PMC 4736873. PMID 26481735.
  41. ↑ Campo, Ilaria; Luisetti, Maurizio; Griese, Matthias; Trapnell, Bruce C.; Bonella, Francesco; Grutters, Jan; Nakata, Koh; Van Moorsel, Coline H. M.; Costabel, Ulrich; Cottin, Vincent; Ichiwata, Toshio; Inoue, Yoshikazu; Braschi, Antonio; Bonizzoni, Giacomo; Iotti, Giorgio A.; Tinelli, Carmine; Rodi, Giuseppe (2016). "Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures". Orphanet Journal of Rare Diseases. 11 (1). doi:10.1186/s13023-016-0497-9. ISSN 1750-1172.
  42. ↑ Michaud, Gaëtane; Reddy, Chakravarthy; Ernst, Armin (2009). "Whole-Lung Lavage for Pulmonary Alveolar Proteinosis". Chest. 136 (6): 1678–1681. doi:10.1378/chest.09-2295. ISSN 0012-3692.
  43. ↑ Kavuru MS, Sullivan EJ, Piccin R, Thomassen MJ, Stoller JK (April 2000). "Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis". Am. J. Respir. Crit. Care Med. 161 (4 Pt 1): 1143–8. doi:10.1164/ajrccm.161.4.9906044. PMID 10764303.
  44. ↑ Borie R, Debray MP, Laine C, Aubier M, Crestani B (June 2009). "Rituximab therapy in autoimmune pulmonary alveolar proteinosis". Eur. Respir. J. 33 (6): 1503–6. doi:10.1183/09031936.00160908. PMID 19483052.
  45. ↑ Luisetti M, Rodi G, Perotti C, Campo I, Mariani F, Pozzi E, Trapnell BC (May 2009). "Plasmapheresis for treatment of pulmonary alveolar proteinosis". Eur. Respir. J. 33 (5): 1220–2. doi:10.1183/09031936.00097508. PMID 19407056.
  46. ↑ Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ (2012). "Pulmonary alveolar proteinosis". Can. Respir. J. 19 (4): 243–5. PMC 3411387. PMID 22891182.
  47. ↑ Patel SM, Sekiguchi H, Reynolds JP, Krowka MJ (2012). "Pulmonary alveolar proteinosis". Can. Respir. J. 19 (4): 243–5. PMC 3411387. PMID 22891182.


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