ADOPTING ORPHAN DISEASES RARE INTERSTITIAL LUNG DISEASES

adoptingorphandiseaseskapak

PULMONARY ALVEOLAR PROTEINOSIS

Nazlı Çetin

Afyonkarahisar State Hospital, Department of Chest Diseases, Afyonkarahisar, Türkiye

Cetin N. Pulmonary Alveolar Proteinosis. In: Altinisik G, McCormack FX, editors. Adopting Orphan Diseases: Rare Interstitial Lung Diseases. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.25-44.

ABSTRACT

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by surfactant accumulation within the alveoli, leading to impaired gas exchange and, in severe cases, respiratory failure. Once regarded as idiopathic, PAP is now classified into autoimmune, secondary, hereditary, and congenital forms based on distinct underlying mechanisms. Autoimmune PAP (aPAP), the most common type, is mediated by GM-CSF autoantibodies that impair macrophage-mediated surfactant clearance. Secondary PAP is typically associated with hematologic malignancies or environmental exposures, while hereditary and congenital types result from genetic defects affecting surfactant metabolism or GMCSF receptor function.

Despite a shared histopathological hallmark, clinical manifestations are heterogeneous, ranging from asymptomatic cases to progressive dyspnea and hypoxemic respiratory failure. Diagnosis relies on clinical suspicion supported by characteristic radiological findings, bronchoalveolar lavage (BAL) cytology, and GM-CSF autoantibody testing. High-resolution CT often reveals the classic “crazy paving” pattern, while milky BAL fluid with PAS-positive material is considered diagnostic in the appropriate clinical context.

Whole lung lavage (WLL) remains the cornerstone of treatment, particularly for symptomatic patients, and is strongly recommended in current guidelines. Inhaled GM-CSF has emerged as an effective and noninvasive alternative for aPAP, with support from randomized controlled trials. Other options, such as rituximab, plasmapheresis, or lung transplantation, may be considered in refractory cases. For secondary and congenital PAP, no standardized treatment exists, and management primarily focuses on treating the underlying condition and providing supportive care.

Prognosis varies depending on PAP subtype, disease severity, and treatment response. While spontaneous remission can occur, close follow-up is essential due to the risks of respiratory failure, infections, and, in rare cases, fibrosis. Advances at the molecular level, novel therapies targeting cholesterol homeostasis and macrophage function, and the expansion of international registries and PAP centers are expected to improve diagnosis, treatment, and outcomes for this complex disease, while also enhancing patient access to specialized care.

Keywords: Autoimmune PAP; Crazy paving; GM-CSF; Pulmonary alveolar proteinosis; Surfactant; Whole lung lavage

Referanslar

  1. Rosen SH, Castleman B, Lıebow AA. Pulmonary alveolar proteinosis. N Engl J Med. 1958;258(23):1123-42. [Crossref]  [PubMed]
  2. Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002;166(2):215-5. [Crossref]  [PubMed]
  3. Dranoff G, Crawford AD, Sadelain M, Ream B, Rashid A, Bronson RT, et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Sci ence. 1994;264(5159):713-6. [Crossref]  [PubMed]
  4. Kitamura T, Tanaka N, Watanabe J, Uchida, Kanegasaki S, Yamada Y, et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med. 1999;190(6):875-80. [Crossref]  [PubMed]  [PMC]
  5. Carnovale R, Zornoza J, Goldman AM, Luna M. Pulmonary alveolar proteinosis: its association with hematologic malignancy and lymphoma. Radiology. 1977;122(2):303 [Crossref]  [PubMed]
  6. Patiroglu T, Akyildiz B, Patiroglu TE, Gulmez IY. Recurrent pulmonary alveolar proteinosis secondary to agammaglobulinemia. Pediatr Pulmonol. 2008;43(7):710-3. [Crossref]  [PubMed]
  7. Shoji N, Ito Y, Kimura Y, Nishimaki J, Kuriyama Y, Tauchi T, et. Pulmonary alveolar proteinosis as a terminal complication in myelodysplastic syndromes: a report of four cases detected on autopsy. Leuk Res. 2002;26(6):591-5. [Crossref]  [PubMed]
  8. Schiller V, Aberle DR, Aberle AM. Pulmonary alveolar proteinosis. Occurrence with metastatic melanoma to lung. Chest. 1989;95(2):466-7. [Crossref]  [PubMed]
  9. Shimizu Y, Matsuzaki S, Dobashi K, Yanagitani N, Satoh T, Koka M, et al. Elemental analysis of lung tissue particles and intracellular iron content of alveolar macrophages in pulmonary alveolar proteinosis. Respir Res. 2011;12(1):88. [Crossref]  [PubMed]  [PMC]
  10. Gacouin A, Le Tulzo Y, Suprin E, Briens E, Bernard M, Camus C, et al. Acute respiratory failure caused by secondary alveolar proteinosis in a patient with acute myeloid leukemia: a case report. Intensive Care Med. 1998;24(3):265- [Crossref]  [PubMed]
  11. Zhang D, Tian X, Feng R, Guo X, Wang P, Situ Y, et al. Secondary pulmonary alveolar proteinosis: a single-center retrospective study (a case series and literature review). BMC Pulm Med. 2018;18(1):15. [Crossref]  [PubMed]  [PMC]
  12. Miller RR, Churg AM, Hutcheon M, Lom S. Pulmonary alveolar proteinosis and aluminum dust exposure. Am Rev Respir Dis. 1984;130(2):312-5. [Crossref]  [PubMed]
  13. Tanaka T, Motoi N, Tsuchihashi Y, Tazawa R, Kaneko C, Nei T, et al. Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB. J Med Genet. 2011;48(3):205-9. [Crossref]  [PubMed]
  14. Hildebrandt J, Yalcin E, Bresser HG, Cinel G, Gappa M, Haghighi A, et al. Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis. Orphanet J Rare Dis. 2014;9:171. [Crossref]  [PubMed]  [PMC]
  15. 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. 2008;205(12):2711-6. [Crossref]  [PubMed]  [PMC]
  16. Trapnell BC, Nakata K, Bonella F, Campo I, Griese M, Hamilton J, et al. Pulmonary alveolar proteinosis. Nat Rev Dis Primers. 2019;5(1):16. [Crossref]  [PubMed]
  17. Ben Dov I, Kishinevski Y, Roznman J, Soliman A, Bishara H, Zelligson E, et al. Pulmonary alveolar proteinosis in Israel: ethnic clustering. Isr Med Assoc J. 1999;1(2):75-8.
  18. Inoue Y, Trapnell BC, Tazawa R, Arai T, Takada T, Hizawa N, et. al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med. 2008;177(7):752-62. [Crossref]  [PubMed]
  19. McCarthy C, Avetisyan R, Carey BC, Chalk C, Trapnell BC. Prevalence and healthcare burden of pulmonary alveolar proteinosis. Orphanet J Rare Dis. 2018;13(1):129. [Crossref]  [PubMed]  [PMC]
  20. Yoon HY, Kim JH, Kim YJ, Song JW. Pulmonary alveolar proteinosis in Korea: analysis of prevalence and incidence via a nationwide population-based study. BMC Pulm Med. 2020;20(1):34. [Crossref]  [PubMed]  [PMC]
  21. Davidson JM, Macleod WM. Pulmonary alveolar proteinosis. Br J Dis Chest. 1969;63(1):13-28. [Crossref]  [PubMed]
  22. Keller CA, Frost A, Cagle PT, Abraham JL. Pulmonary alveolar proteinosis in a painter with elevated pulmonary concentrations of titanium. Chest. 1995;108(1):277-80. [Crossref]  [PubMed]
  23. Cummings KJ, Donat WE, Ettensohn DB, Roggli VL, Ingram P, Kreiss K. Pulmonary alveolar proteinosis in workers at an indium processing facility. Am J Respir Crit Care Med. 2010;181(5):458-64. [Crossref]  [PubMed]
  24. Salvaterra E, Campo I. Pulmonary alveolar proteinosis: from classification to therapy. Breathe (Sheff). 2020;16(2):200018. [Crossref]  [PubMed]  [PMC]
  25. Jouneau S, Ménard C, Lederlin M. Pulmonary alveolar proteinosis. Respirology. 2020;25(8):816-26. [Crossref]  [PubMed]
  26. Gower WA, Nogee LM. Surfactant dysfunction. Paediatr Respir Rev. 2011;12(4):223-9. [Crossref]  [PubMed]  [PMC]
  27. Ishii H, Seymour JF, Tazawa R, Inoue Y, Uchida N, Nishida A, et al. Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan. BMC Pulm Med. 2014;14:37. [Crossref]  [PubMed]  [PMC]
  28. Wright JR. Immunomodulatory functions of surfactant. Physiol Rev. 1997;77(4):931-62. [Crossref]  [PubMed]
  29. Perez-Gil J, Weaver TE. Pulmonary surfactant pathophysiology: current models and open questions. Physiology (Bethesda). 2010;25(3):132-41. [Crossref]  [PubMed]
  30. Lehtonen A, Matikainen S, Miettinen M, Julkunen I. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J Leukoc Biol. 2002;71(3):511-9. [Crossref]
  31. Shibata Y, Berclaz PY, Chroneos ZC, Yoshida M, Whitsett JA, Trapnell BC. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001;15(4):557-67. [Crossref]  [PubMed]
  32. Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M, Powell J, et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell. 2008;134(3):496-507. [Crossref]  [PubMed]
  33. Gearing DP, King JA, Gough NM, Nicola NA. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 1989;8(12):3667-76. [Crossref]  [PubMed]  [PMC]
  34. Yancey PG, Jerome WG. Lysosomal sequestration of free and esterified cholesterol from oxidized low density lipoprotein in macrophages of different species. J Lipid Res. 1998;39(7):1349-61. [Crossref]
  35. Sakagami T, Beck D, Uchida K, Suzuki T, Carey BC, Nakata K, et al. Patient-derived granulocyte/macrophage colony-stimulating factor autoantibodies reproduce pulmonary alveolar proteinosis in nonhuman primates. Am J Respir Crit Care Med. 2010;182(1):49-61. [Crossref]  [PubMed]
  36. Uchida K, Nakata K, Carey B, Chalk C, Suzuki T, Sakagami T, et al. Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis. J Immunol Methods. 2014;402(12):57-70. [Crossref]  [PubMed]  [PMC]
  37. Uchida K, Nakata K, Suzuki T, Luisetti M, Watanabe M, Koch DE, et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood. 2009;113(11):2547-56. [Crossref]  [PubMed]  [PMC]
  38. Bendtzen K, Svenson M, Hansen MB. GM-CSF autoantibodies in pulmonary alveolar proteinosis. N Engl J Med. 2007;356(19):2001-2. [Crossref]  [PubMed]
  39. CLSI. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline-Third Edition. [Internet] CLSI document C28-A3c. Wayne, PA: Clinical and Laboratory Standards Institute; 2008. [Accessed date: 09.07.2025] org/preview-pages/CLSI/ [Link]
  40. McCarthy C, Carey BC, Trapnell BC. Autoimmune Pulmonary Alveolar Proteinosis. Am J Respir Crit Care Med. 2022;205(9):1016-35. [Crossref]  [PubMed]
  41. Seymour JF, Doyle IR, Nakata K, Presneill JJ, Schoch OD, Hamano E, 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. 2003;58(3):252-7. [Crossref]  [PubMed]  [PMC]
  42. Burmester GR, McInnes IB, Kremer JM, Miranda P, Vencovský J, Godwood A, et al. Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor-Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2018;70(5):679-89. [Crossref]  [PubMed]  [PMC]
  43. Uchida K, Nakata K, Trapnell BC, Terakawa T, Hamano E, Mikami A, et al. High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood. 2004;103(3):1089-98. [Crossref]  [PubMed]
  44. Wang Y, Thomson CA, Allan LL, Jackson LM, Olson M, Hercus TR, et al. Characterization of pathogenic human monoclonal autoantibodies against GM-CSF. Proc Natl Acad Sci U S A. 2013;110(19):7832-7. [Crossref]  [PubMed]  [PMC]
  45. 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. 2008;205(12):2703-10. [Crossref]  [PubMed]  [PMC]
  46. Suzuki T, Maranda B, Sakagami T, Catellier P, Couture CY, Carey BC, et al. Hereditary pulmonary alveolar proteinosis caused by recessive CSF2RB mutations. Eur Respir J. 2011;37(1):201-4. [Crossref]  [PubMed]
  47. Suzuki T, Sakagami T, Young LR, Carey BC, Wood RE, Luisetti M, et al. Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med. 2010;182(10):1292-304. [Crossref]  [PubMed]
  48. Chiu CY, Su SC, Fan WL, Lai SH, Tsai MH, Chen SH, et al. Whole-Genome Sequencing of a Family with Hereditary Pulmonary Alveolar Proteinosis Identifies a Rare Structural Variant Involving CSF2RA/CRLF2/IL3RA Gene Dis ruption. Sci Rep. 2017;7:43469. [Crossref]  [PubMed]  [PMC]
  49. Al-Haidary AS, Alotaibi W, Alhaider SA, Al-Saleh S. A newly identified novel variant in the CSF2RA gene in a child with pulmonary alveolar proteinosis: a case report. J Med Case Rep. 2017;11(1):122. [Crossref]  [PubMed]  [PMC]
  50. Hadchouel A, Drummond D, Abou Taam R, Lebourgeois M, Delacourt C, de Blic J. Alveolar proteinosis of genetic origins. Eur Respir Rev. 2020;29(158):190187. [Crossref]  [PubMed]  [PMC]
  51. Forbes A, Pickell M, Foroughian M, Yao LJ, Lewis J, Veldhuizen R. Alveolar macrophage depletion is associated with increased surfactant pool sizes in adult rats. J Appl Physiol (1985). 2007;103(2):637-45. [Crossref]  [PubMed]
  52. Yokomura K, Chida K, Suda T, Miwa S, Nakano H, Kuwata H, et al. Secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome. Nihon Kokyuki Gakkai Zasshi. 2002;40(7):599-604. [Crossref]  [PubMed]
  53. Kita H, Muro S, Nakano Y, Hattori N, Mizutani T, Kagioka H, et al. An autopsy case of acute lymphocytic leukemia associated with secondary pulmonary alveolar proteinosis and systemic aspergillosis. Nihon Kyobu Shikkan Gakkai Zasshi. 1993;31(3):374-8. [Crossref]
  54. Birsak CA, van Rossem RN, Nijhuis-Heddes JM, Maartense E. Pulmonary alveolar proteinosis: a complication in patients with hematologic malignancy. Neth J Med. 2000;56(5):193-7. [Crossref]  [PubMed]
  55. Ishii H, Tazawa R, Kaneko C, Saraya T, Inoue Y, Hamano E, et al. Clinical features of secondary pulmonary alveolar proteinosis: pre-mortem cases in Japan. Eur Respir J. 2011;37(2):465-8. [Crossref]  [PubMed]
  56. El Kik A, Vander Kuylen M, Bailly B, Fallas J, Bondue B. Unusual cause of dyspnea in patient with Myelofibrosis: The Ruxolitinib lung. Respir Med Case Rep. 2024;51:102090. [Crossref]  [PubMed]  [PMC]
  57. Bedrossian CW, Luna MA, Conklin RH, Miller WC. Alveolar proteinosis as a consequence of immunosuppression. A hypothesis based on clinical and pathologic observations. Hum Pathol. 1980;11(5 Suppl):527-35.
  58. Lopez P, Kohler S, Dimri S. Interstitial Lung Disease Associated with mTOR Inhibitors in Solid Organ Transplant Recipients: Results from a Large Phase III Clinical Trial Program of Everolimus and Review of the Literature. J Transplant. 2014;2014:305931. [Crossref]  [PubMed]  [PMC]
  59. Hinojosa-González DE, Dávila-González D, Salgado-Garza G, Flores-Villalba E. Reversible sirolimus-induced pulmonary alveolar proteinosis in a renal transplant patient. Lung India. 2020;37(3):252-6. [Crossref]  [PubMed]  [PMC]
  60. Punatar AD, Kusne S, Blair JE, Seville MT, Vikram HR. Opportunistic infections in patients with pulmonary alveolar proteinosis. J Infect. 2012;65(2):173-9. [Crossref]  [PubMed]
  61. Heppleston AG, Wright NA, Stewart JA. Experimental alveolar lipo-proteinosis following the inhalation of silica. J Pathol. 1970;101(4):293-307. [Crossref]  [PubMed]
  62. Heppleston AG, Fletcher K, Wyatt I. Changes in the composition of lung lipids and the “turnover” of dipalmitoyl lecithin in experimental alveolar lipo-proteinosis induced by inhaled quartz. Br J Exp Pathol. 1974;55(4):384-95. [Crossref]  [PubMed]
  63. Xipell JM, Ham KN, Price CG, Thomas DP. Acute silicoproteinosis. Thorax. 1977;32(1):104-11. [Crossref]  [PubMed]  [PMC]
  64. Bonella F, Bauer PC, Griese M, Ohshimo S, Guzman J, Costabel U. Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients. Respir Med. 2011;105(12):1908-16. [Crossref]  [PubMed]
  65. McDonald JW, Alvarez F, Keller CA. Pulmonary alveolar proteinosis in association with household exposure to fibrous insulation material. Chest. 2000;117(6):1813-7. [Crossref]  [PubMed]
  66. Johansson A, Camner P. Adverse effects of metals on the alveolar part of the lung. Scan Electron Microsc. 1986;(Pt 2):631-7.
  67. Santos GF, Portela J, Argyropoulou D, Varudo R, Pimenta I, Oliveira A, et al. Alveolar proteinosis due to toxic inhalation at workplace. Respir Med Case Rep. 2020;31:101199. [Crossref]  [PubMed]  [PMC]
  68. Costabel U, Nakata K. Pulmonary alveolar proteinosis associated with dust inhalation: not secondary but autoimmune? Am J Respir Crit Care Med. 2010;181(5):427-8. [Crossref]  [PubMed]
  69. Mechri M, Epaud R, Emond S, Coulomb A, Jaubert F, Tarrant A, et al. Surfactant protein C gene (SFTPC) mutation-associated lung disease: high-resolution computed tomography (HRCT) findings and its relation to histological analysis. Pediatr Pulmonol. 2010;45(10):1021-9. [Crossref]  [PubMed]
  70. Guillot L, Carré A, Szinnai G, Castanet M, Tron E, Jaubert F, et al. NKX2-1 mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”. Hum Mutat. 2010;31(2):E1146-E1162. [Crossref]  [PubMed]
  71. Young LR, Nogee LM, Barnett B, Panos RJ, Colby TV, Deutsch GH. Usual interstitial pneumonia in an adolescent with ABCA3 mutations. Chest. 2008;134(1):192-5. [Crossref]  [PubMed]
  72. Borie R, Danel C, Debray MP, Taille C, Dombret MC, Aubier M, et al. Pulmonary alveolar proteinosis. Eur Respir Rev. 2011;20(120):98-107. [Crossref]  [PubMed]  [PMC]
  73. Shah PL, Hansell D, Lawson PR, Reid KB, Morgan C. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000;55(1):67-77. [Crossref]  [PubMed]  [PMC]
  74. Morton C, DeBiasi E. Pulmonary Alveolar Proteinosis. Clin Chest Med. 2025;46(2):373-82. [Crossref]  [PubMed]
  75. McCarthy C, Carey B, Trapnell BC. Blood Testing for Differential Diagnosis of Pulmonary Alveolar Proteinosis Syndrome. Chest. 2019;155(2):450-2. [Crossref]  [PubMed]  [PMC]
  76. Lee KN, Levin DL, Webb WR, Chen D, Storto ML, Golden JA. Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and functional correlations. Chest. 1997;111(4):989-95. [Crossref]  [PubMed]
  77. Holbert JM, Costello P, Li W, Hoffman RM, Rogers RM. CT features of pulmonary alveolar proteinosis. AJR Am J Roentgenol. 2001;176(5):1287-94. [Crossref]  [PubMed]
  78. Hawkins P, Chawke L, Cormican L, Wikenheiser-Brokamp KA, Fabre A, Keane MP, et al. Autoimmune pulmonary alveolar proteinosis: a discrepancy between symptoms and CT findings. Lancet. 2021;398(10296):e7. [Crossref]  [PubMed]
  79. Ishii H, Trapnell BC, Tazawa R, Inoue Y, Akira M, Kogure Yet al. Japanese Center of the Rare Lung Disease Consortium. Comparative study of high-resolution CT findings between autoimmune and secondary pulmonary alveolar proteinosis. Chest. 2009;136(5):1348-55. [Crossref]  [PubMed]
  80. Johkoh T, Itoh H, Müller NL, Ichikado K, Nakamura H, Ikezoe J, et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology. 1999;211(1):155-60. [Crossref]  [PubMed]
  81. Altınışık G, Çetin N, Uğurlu E, Akbudak İH, Başer S. PAP with COVID-19 Radiology Differential Diagnosis Discussion. Turk Thorac J. 2021;22(1):99-100. [Crossref]  [PubMed]
  82. Wells AU. The clinical utility of bronchoalveolar lavage in diffuse parenchymal lung disease. Eur. Respir. Rev. 2010;19(117):237–41. [Crossref]  [PubMed]  [PMC]
  83. McCarthy C, Bonella F, O’Callaghan M, Dupin C, Alfaro T, Fally M, et al. European Respiratory Society guidelines for the diagnosis and management of pulmonary alveolar proteinosis. Eur Respir J. 2024;64(5):2400725. [Crossref]  [PubMed]
  84. Azuma K, Takimoto T, Kasai T, Hirose M, Hatsuda K, Sugimoto C, et al. Diagnostic yield and safety of bronchofiberscopy for pulmonary alveolar proteinosis. Respir Investig. 2021;59(6):757-65. [Crossref]  [PubMed]
  85. Suzuki T, Trapnell BC. Pulmonary Alveolar Proteinosis Syndrome. Clin Chest Med. 2016;37(3):431-40. [Crossref]  [PubMed]  [PMC]
  86. Zhao YY, Huang H, Liu YZ, Song XY, Li S, Xu ZJ. Whole Lung Lavage Treatment of Chinese Patients with Autoimmune Pulmonary Alveolar Proteinosis: A Retrospective Long-term Follow-up Study. Chin Med J (Engl). 2015;128(20):2714-9. [Crossref]  [PubMed]  [PMC]
  87. Ben-Abraham R, Greenfeld A, Rozenman J, Ben-Dov I. Pulmonary alveolar proteinosis: step-by-step perioperative care of whole lung lavage procedure. Heart Lung. 2002;31(1):43-9. [Crossref]  [PubMed]
  88. Wasserman K, Blank N, Fletcher G. Lung lavage (alveolar washing) in alveolar proteinosis. Am J Med. 1968;44(4):611- [Crossref]  [PubMed]
  89. Campo I, Luisetti M, Griese M, Trapnell BC, Bonella F, Grutters J, et al; WLL International Study Group. Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures. Orphanet J Rare Dis. 2016;11(1):115. [Crossref]  [PubMed]  [PMC]
  90. Altinisik G, Yigit N, Metin B, Turkarslan M, Akbudak IH. A Case of Pulmonary Alveolar Proteinosis in which a New Approach to the Traditional Whole Lung Lavage Technique is Preformed. Respir Case Rep. 2022;11(1):36-40. [Crossref]
  91. Ra SW, Park SE, Lee HK, Han IS, Park SH. Whole lung lavage using a rapid infusion system to treat a patient with pulmonary alveolar proteinosis. Yeungnam Univ J Med. 2020;37(1):67-72. [Crossref]  [PubMed]  [PMC]
  92. Wayne MT, Ali MS, Roller L, Gay SE, Maldonado F, De Cardenas J. Safety of Bilateral Whole Lung Lavage for Pulmonary Alveolar Proteinosis: Experiences in a Multicenter Cohort. J Bronchology Interv Pulmonol. 2023;30(2):188- [Crossref]  [PubMed]
  93. Paschen C, Reiter K, Stanzel F, Teschler H, Griese M. Therapeutic lung lavages in children and adults. Respir Res. 2005;6(1):138. [Crossref]  [PubMed]  [PMC]
  94. Awab A, Khan MS, Youness HA. Whole lung lavage-technical details, challenges and management of complications. J Thorac Dis. 2017;9(6):1697-706. [Crossref]  [PubMed]  [PMC]
  95. Sikachi R, Anders M. Whole lung lavage: considerations from the anesthesiology perspective. Curr Opin Pulm Med. 2025;31(1):53-8. [Crossref]  [PubMed]
  96. Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S, et al. Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. N Engl J Med. 2019;381(10):923-32. [Crossref]  [PubMed]
  97. Trapnell BC, Inoue Y, Bonella F, Morgan C, Jouneau S, Bendstrup E, et al; IMPALA Trial Investigators. Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2020;383(17):1635-44.
  98. Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2010;181(12):1345-54. [Crossref]  [PubMed]
  99. Seymour JF, Presneill JJ, Schoch OD, Downie GH, Moore PE, Doyle IR, et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med. 2001;163(2):524-31. [Crossref]  [PubMed]
  100. Wylam ME, Ten R, Prakash UB, Nadrous HF, Clawson ML, Anderson PM. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur Respir J. 2006;27(3):585-93. [Crossref]  [PubMed]
  101. Venkateshiah SB, Yan TD, Bonfield TL, Thomassen MJ, Meziane M, Czich C, et al. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest. 2006;130(1):227-37. [Crossref]  [PubMed]
  102. Papiris SA, Tsirigotis P, Kolilekas L, Papadaki G, Papaioannou AI, Triantafillidou C, et al. Long-term inhaled granulocyte macrophage-colony-stimulating factor in autoimmune pulmonary alveolar proteinosis: effectiveness, safety, and lowest effective dose. Clin Drug Investig. 2014;34(8):553- [Crossref]  [PubMed]
  103. Zhang F, Weng D, Su Y, Yin C, Shen L, Zhang Y, et al. Therapeutic effect of subcutaneous injection of low dose recombinant human granulocyte-macrophage colony-stimulating factor on pulmonary alveolar proteinosis. Respir Res. 2020;21(1):1. [Crossref]  [PubMed]  [PMC]
  104. Zhen G, Li D, Jiang J, Weng Y. Granulocyte-Macrophage Colony-Stimulating Factor Inhalation Therapy for Severe Pulmonary Alveolar Proteinosis. Am J Ther. 2020;28(2):e171-e178. [Crossref]  [PubMed]
  105. Campo I, Carey BC, Paracchini E, Kadija Z, De Silvestri A, Rodi G, et al. Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients. Eur Respir J. 2024;63(1):2301233. [Crossref]  [PubMed]  [PMC]
  106. Kavuru MS, Malur A, Marshall I, Barna BP, Meziane M, Huizar I, et al. An open-label trial of rituximab therapy in pulmonary alveolar proteinosis. Eur Respir J. 2011;38(6):1361- [Crossref]  [PubMed]  [PMC]
  107. Soyez B, Borie R, Menard C, Cadranel J, Chavez L, Cottin V, et al. Rituximab for auto-immune alveolar proteinosis, a real life cohort study. Respir Res. 2018;19(1):74. [Crossref]  [PubMed]  [PMC]
  108. Parker LA, Novotny DB. Recurrent alveolar proteinosis following double lung transplantation. Chest. 1997;111:1457– [Crossref]  [PubMed]
  109. Lachmann N, Happle C, Ackermann M, Lüttge D, Wetzke M, Merkert S, et al. Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2014;189(2):167-82. [Crossref]  [PubMed]
  110. McCarthy C, Lee E, Bridges JP, Sallese A, Suzuki T, Woods JC, et al. Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. Nat Commun. 2018;9(1):3127. [Crossref]  [PubMed]  [PMC]
  111. Akasaka K, Tanaka T, Kitamura N, Ohkouchi S, Tazawa R, Takada T, et al. Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study. BMC Pulm Med. 2015;15:88. [Crossref]  [PubMed]  [PMC]
  112. Chaulagain CP, Pilichowska M, Brinckerhoff L, Tabba M, Erban JK. Secondary pulmonary alveolar proteinosis in hematologic malignancies. Hematol Oncol Stem Cell Ther. 2014;7(4):127-35. [Crossref]  [PubMed]
  113. Gaine SP, O’Marcaigh AS. Pulmonary alveolar proteinosis: lung transplant or bone marrow transplant? Chest;113(2):563-4. [Crossref]  [PubMed]
  114. Huang J, Xie S, Gao Y, Lin Z, Xu Z, Lin J, et al. Phenotypic heterogeneity in mortality and prognosis of pulmonary alveolar proteinosis: a large-scale, global pooled analysis of individual-level data. Orphanet J Rare Dis. 2025;20(1):102. [Crossref]  [PubMed]  [PMC]
  115. Guirriec Y, Luque-Paz D, Bernard G, Mabo A, Kerjouan M, Ménard C, et al; OrphaLung network. Pulmonary fibrosis in patients with autoimmune pulmonary alveolar proteinosis: a retrospective nationwide cohort study. ERJ Open Res. 2024;10(6):00314-2024. [Crossref]  [PubMed]  [PMC]
  116. Altınışık G. As our hearts keep beating “From the notebook of a physician” Timişoara: Victor Babeş” Publishing House. 2024:101-13 uploads/2024/06/EVB_Beletristica_As-Our-Hearts-Keep- Beating_2024.pdf [Link]