Pulmonary alveolar proteinosis

Abstract

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages. PAP results in progressive dyspnoea of insidious onset, hypoxaemic respiratory failure, secondary infections and pulmonary fibrosis. PAP can be classified into different types on the basis of the pathogenetic mechanism: primary PAP is characterized by the disruption of granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling and can be autoimmune (caused by elevated levels of GM-CSF autoantibodies) or hereditary (due to mutations in CSF2RA or CSF2RB, encoding GM-CSF receptor subunits); secondary PAP results from various underlying conditions; and congenital PAP is caused by mutations in genes involved in surfactant production. In most patients, pathogenesis is driven by reduced GM-CSF-dependent cholesterol clearance in alveolar macrophages, which impairs alveolar surfactant clearance. PAP has a prevalence of at least 7 cases per million individuals in large population studies and affects men, women and children of all ages, ethnicities and geographical locations irrespective of socioeconomic status, although it is more-prevalent in smokers. Autoimmune PAP accounts for >90% of all cases. Management aims at improving symptoms and quality of life; whole-lung lavage effectively removes excessive surfactant. Novel pathogenesis-based therapies are in development, targeting GM-CSF signalling, immune modulation and cholesterol homeostasis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Alveolar surfactant homeostasis and its disruption in PAP.
Fig. 2: Algorithm for the differential diagnosis of PAP.
Fig. 3: Radiological findings in PAP.
Fig. 4: Currently available and emerging therapies to treat patients with PAP.

References

  1. 1.

    Rosen, S. G., Castleman, B. & Liebow, A. A. Pulmonary alveolar proteinosis. N. Engl. J. Med. 258, 1123–1142 (1958).

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Seymour, J. F. & Presneill, J. J. Pulmonary alveolar proteinosis: progress in the first 44 years. Am. J. Respir. Crit. Care Med. 166, 215–235 (2002). This article is the first comprehensive review of PAP based on all patients (410) reported in the first 44 years after the initial description by S. G. Rosen in 1958.

    Article  PubMed  Google Scholar 

  3. 3.

    Trapnell, B. C., Whitsett, J. A. & Nakata, K. Pulmonary alveolar proteinosis. N. Engl. J. Med. 349, 2527–2539 (2003). This article reports that GM-CSF autoantibodies are markedly elevated in autoimmune PAP but not in patients with secondary PAP, congenital PAP, other lung diseases or healthy people.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Trapnell, B. C. & Luisetti, M. in Murray & Nadel’s Textbook of Respiratory Medicine Ch. 70 (eds Mason, R. J., Murray, J. F. & Broaddus, V. C.) (Elsevier Health Sciences, 2015).

  5. 5.

    Stanley, E. 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 91, 5592–5596 (1994).

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Dranoff, G. et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 264, 713–716 (1994).

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Kitamura, T. et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 162, 658–662 (2000).

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    McCarthy, C., Avetisyan, R., Carey, B. C., Chalk, C. & Trapnell, B. C. Prevalence and healthcare burden of pulmonary alveolar proteinosis. Orphanet J. Rare Dis. 13, 129 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Inoue, Y. et al. Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am. J. Respir. Crit. Care Med. 177, 752–762 (2008). This comprehensive review is the first to specifically focus on autoimmune PAP.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    McCarthy, C. et al. Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. Nat. Commun. 9, 3127 (2018). This article reports that in patients with autoimmune PAP, esterified cholesterol is the material accumulating in alveolar macrophages, the ratio of cholesterol to total phospholipids in surfactant is markedly increased and oral statin therapy is associated with marked clinical improvement.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Martinez-Moczygemba, M. et al. Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1. J. Exp. Med. 205, 2711–2716 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Suzuki, T. et al. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J. Exp. Med. 205, 2703–2710 (2008). This report and that of Martinez-Moczygemba et al. (2008) were the first reports of hereditary PAP caused by CSF2RA mutations.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Suzuki, T. et al. Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am. J. Respir. Crit. Care Med. 182, 1292–1304 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Suzuki, T. et al. Hereditary pulmonary alveolar proteinosis caused by recessive CSF2RB mutations. Eur. Respir. J. 37, 201–204 (2011).

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Tanaka, T. et al. Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB. J. Med. Genet. 48, 205–209 (2011).

    Article  PubMed  Google Scholar 

  16. 16.

    Ito, M. et al. Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile. BMC Pulm. Med. 17, 40 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Chiu, C. Y. et al. Whole-genome sequencing of a family with hereditary pulmonary alveolar proteinosis identifies a rare structural variant involving CSF2RA/CRLF2/IL3RA gene disruption. Sci. Rep. 7, 43469 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Hildebrandt, J. et al. Characterization of CSF2RA mutation related juvenile pulmonary alveolar proteinosis. Orphanet J. Rare Dis. 9, 171 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Cordonnier, C., Fleury-Feith, J., Escudier, E., Atassi, K. & Bernaudin, J. F. Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am. J. Respir. Crit. Care Med. 149, 788–794 (1994).

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Humble, S., Allan Tucker, J., Boudreaux, C., King, J. A. & Snell, K. Titanium particles identified by energy-dispersive X-ray microanalysis within the lungs of a painter at autopsy. Ultrastruct. Pathol. 27, 127–129 (2003).

    Article  PubMed  Google Scholar 

  21. 21.

    Ishii, H. et al. Secondary pulmonary alveolar proteinosis complicating myelodysplastic syndrome results in worsening of prognosis: a retrospective cohort study in Japan. BMC Pulm. Med. 14, 37 (2014). This article reports on a large cohort of patients with secondary PAP.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Ishii, H. et al. Clinical features of secondary pulmonary alveolar proteinosis: pre-mortem cases in Japan. Eur. Respir. J. 37, 465–468 (2011).

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Israel, R. H. & Magnussen, C. R. Are AIDS patients at risk for pulmonary alveolar proteinosis? Chest 96, 641–642 (1989).

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Kita, H. et al. An autopsy case of acute lymphocytic leukemia associated with secondary pulmonary alveolar proteinosis and systemic aspergillosis [Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi 31, 374–378 (1993).

    CAS  PubMed  Google Scholar 

  25. 25.

    Ladeb, S. et al. Secondary alveolar proteinosis in cancer patients. Support. Care Cancer 4, 420–426 (1996).

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Miller, R. R., Churg, A. M., Hutcheon, M. & Lom, S. Pulmonary alveolar proteinosis and aluminum dust exposure. Am. Rev. Respir. Dis. 130, 312–315 (1984).

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Ohnishi, T. et al. Secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome. Intern. Med. 42, 187–190 (2003).

    Article  PubMed  Google Scholar 

  28. 28.

    Patiroglu, T., Akyildiz, B., Patiroglu, T. E. & Gulmez, I. Y. Recurrent pulmonary alveolar proteinosis secondary to agammaglobulinemia. Pediatr. Pulmonol. 43, 710–713 (2008).

    Article  PubMed  Google Scholar 

  29. 29.

    Philippot, Q. et al. Secondary pulmonary alveolar proteinosis after lung transplantation: a single-centre series. Eur. Respir. J. 49, 1601369 (2017).

    Article  PubMed  Google Scholar 

  30. 30.

    Ruben, F. L. & Talamo, T. S. Secondary pulmonary alveolar proteinosis occurring in two patients with acquired immune deficiency syndrome. Am. J. Med. 80, 1187–1190 (1986).

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Xipell, J. M., Ham, K. N., Price, C. G. & Thomas, D. P. Acute silicoproteinosis. Thorax 32, 104–111 (1977).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Griese, M. Pulmonary alveolar proteinosis: a comprehensive clinical perspective. Pediatrics 140, e20170610 (2017).

    Article  PubMed  Google Scholar 

  33. 33.

    Nogee, L. M., de Mello, D. E., Dehner, L. P. & Colten, H. R. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N. Engl. J. Med. 328, 406–410 (1993).

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Nogee, L. M. et al. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J. Clin. Invest. 93, 1860–1863 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Ballard, P. L. et al. Partial deficiency of surfactant protein B in an infant with chronic lung disease. Pediatrics 96, 1046–1052 (1995).

    CAS  PubMed  Google Scholar 

  36. 36.

    Nogee, L. M. et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N. Engl. J. Med. 344, 573–579 (2001).

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Hamvas, A. et al. Progressive lung disease and surfactant dysfunction with a deletion in surfactant protein C gene. Am. J. Respir. Cell. Mol. Biol. 30, 771–776 (2004).

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Nogee, L. M. Genetic mechanisms of surfactant deficiency. Biol. Neonate 85, 314–318 (2004).

    Article  PubMed  Google Scholar 

  39. 39.

    Shulenin, S. et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N. Engl. J. Med. 350, 1296–1303 (2004).

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Bullard, J. E., Wert, S. E., Whitsett, J. A., Dean, M. & Nogee, L. M. ABCA3 mutations associated with pediatric interstitial lung disease. Am. J. Respir. Crit. Care Med. 172, 1026–1031 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Gower, W. A. & Nogee, L. M. Surfactant dysfunction. Paediatr. Respir. Rev. 12, 223–229 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Keller, C. A., Frost, A., Cagle, P. T. & Abraham, J. L. Pulmonary alveolar proteinosis in a painter with elevated pulmonary concentrations of titanium. Chest 108, 277–280 (1995).

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Cummings, K. J. et al. Pulmonary alveolar proteinosis in workers at an indium processing facility. Am. J. Respir. Crit. Care Med. 181, 458–464 (2010).

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Davidson, J. M. & Macleod, W. M. Pulmonary alveolar proteinosis. Br. J. Dis. Chest. 63, 13–28 (1969).

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Ziskind, M., Jones, R. N. & Weill, H. Silicosis. Am. Rev. Respir. Dis. 113, 643–665 (1976).

    CAS  PubMed  Google Scholar 

  46. 46.

    Heppleston, A. G., Wright, N. A. & Stewart, J. A. Experimental alveolar lipo-proteinosis following the inhalation of silica. J. Pathol. 101, 293–307 (1970).

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Heppleston, A. G., 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. 55, 384–395 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Whitsett, J. A., Wert, S. E. & Weaver, T. E. Diseases of pulmonary surfactant homeostasis. Annu. Rev. Pathol. 10, 371–393 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Perez-Gil, J. & Weaver, T. E. Pulmonary surfactant pathophysiology: current models and open questions. Physiology 25, 132–141 (2010).

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Veldhuizen, R., Nag, K., Orgeig, S. & Possmayer, F. The role of lipids in pulmonary surfactant. Biochim. Biophys. Acta 1408, 90–108 (1998).

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Gearing, D. P., King, J. A., Gough, N. M. & Nicola, N. A. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 8, 3667–3676 (1989).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Hayashida, K. et al. Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor. Proc. Natl Acad. Sci. USA 87, 9655–9659 (1990).

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    D’Andrea, R. J. & Gonda, T. J. A model for assembly and activation of the GM-CSF, IL-3 and IL-5 receptors: insights from activated mutants of the common beta subunit. Exp. Hematol. 28, 231–243 (2000).

    Article  PubMed  Google Scholar 

  54. 54.

    Matsuguchi, T., Zhao, Y., Lilly, M. B. & Kraft, A. S. The cytoplasmic domain of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha subunit is essential for both GM-CSF-mediated growth and differentiation. J. Biol. Chem. 272, 17450–17459 (1997).

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Watanabe, S., Itoh, T. & Arai, K. Roles of JAK kinases in human GM-CSF receptor signal transduction. J. Allergy Clin. Immunol. 98, S183–S191 (1996).

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    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. 71, 511–519 (2002).

    CAS  PubMed  Google Scholar 

  57. 57.

    Shibata, Y. et al. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 15, 557–567 (2001).

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Schneider, C. et al. Induction of the nuclear receptor PPAR-gamma by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat. Immunol. 15, 1026–1037 (2014).

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Bonfield, T. L. et al. PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L1132–L1136 (2003).

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Moore, K. J. et al. The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat. Med. 7, 41–47 (2001).

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Sallese, A. et al. Targeting cholesterol homeostasis in lung diseases. Sci. Rep. 7, 10211 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Berclaz, P. Y., Shibata, Y., Whitsett, J. A. & Trapnell, B. C. GM-CSF, via PU.1, regulates alveolar macrophage Fcgamma R-mediated phagocytosis and the IL-18/IFN-gamma -mediated molecular connection between innate and adaptive immunity in the lung. Blood 100, 4193–4200 (2002).

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Berclaz, P. Y. et al. Endocytic internalization of adenovirus, nonspecific phagocytosis, and cytoskeletal organization are coordinately regulated in alveolar macrophages by GM-CSF and PU.1. J. Immunol. 169, 6332–6342 (2002).

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Berclaz, P. Y. et al. GM-CSF regulates a PU.1-dependent transcriptional program determining the pulmonary response to LPS. Am. J. Respir. Cell. Mol. Biol. 36, 114–121 (2007).

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Uchida, K. et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N. Engl. J. Med. 356, 567–579 (2007).

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    LeVine, A. M., Reed, J. A., Kurak, K. E., Cianciolo, E. & Whitsett, J. A. GM-CSF-deficient mice are susceptible to pulmonary group B streptococcal infection. J. Clin. Invest. 103, 563–569 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Paine, R. 3rd et al. Granulocyte-macrophage colony-stimulating factor in the innate immune response to Pneumocystis carinii pneumonia in mice. J. Immunol. 164, 2602–2609 (2000).

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    Paine, R. 3rd et al. Impaired functional activity of alveolar macrophages from GM-CSF- deficient mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L1210–L1218 (2001).

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Seymour, J. F. et al. Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood 90, 3037–3049 (1997).

    CAS  PubMed  Google Scholar 

  70. 70.

    Zhan, Y., Lieschke, G. J., Grail, D., Dunn, A. R. & Cheers, C. Essential roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF in the sustained hematopoietic response of Listeria monocytogenes-infected mice. Blood 91, 863–869 (1998).

    CAS  PubMed  Google Scholar 

  71. 71.

    Riopel, J., Tam, M., Mohan, K., Marino, M. W. & Stevenson, M. M. Granulocyte-macrophage colony-stimulating factor-deficient mice have impaired resistance to blood-stage malaria. Infect. Immun. 69, 129–136 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Gonzalez-Juarrero, M. et al. Disruption of granulocyte macrophage-colony stimulating factor production in the lungs severely affects the ability of mice to control Mycobacterium tuberculosis infection. J. Leukoc. Biol. 77, 914–922 (2005).

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Ballinger, M. N. et al. Role of granulocyte macrophage colony-stimulating factor during gram-negative lung infection with Pseudomonas aeruginosa. Am. J. Respir. Cell. Mol. Biol. 34, 766–774 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Seymour, J. F. Extra-pulmonary aspects of acquired pulmonary alveolar proteinosis as predicted by granulocyte-macrophage colony-stimulating factor-deficient mice. Respirology 11 (Suppl.), S16–S22 (2006).

    Article  PubMed  Google Scholar 

  75. 75.

    Carey, B., Staudt, M. K., Bonaminio, D., van der Loo, J. C. & Trapnell, B. C. PU.1 redirects adenovirus to lysosomes in alveolar macrophages, uncoupling internalization from infection. J. Immunol. 178, 2440–2447 (2007).

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Spight, D., Trapnell, B., Zhao, B., Berclaz, P. & Shanley, T. P. Granulocyte-macrophage-colony-stimulating factor-dependent peritoneal macrophage responses determine survival in experimentally induced peritonitis and sepsis in mice. Shock 30, 434–442 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Huang, F. F. et al. GM-CSF in the lung protects against lethal influenza infection. Am. J. Respir. Crit. Care Med. 184, 259–268 (2011).

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Ikegami, M. et al. Surfactant metabolism in transgenic mice after granulocyte macrophage-colony stimulating factor ablation. Am. J. Physiol. 270, L650–L658 (1996).

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Yoshida, M., Ikegami, M., Reed, J. A., Chroneos, Z. C. & Whitsett, J. A. GM-CSF regulates surfacant Protein-A and lipid catabolism by alveolar macrohpages. Am. J. Physiol. Lung Cell. Mol. Physiol. 280, L379–L386 (2001).

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Nishinakamura, R. et al. Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor- deficient mice are normal. Immunity 2, 211–222 (1995).

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Robb, L. et al. Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. Proc. Natl Acad. Sci. USA 92, 9565–9569 (1995). This report is the first on hereditary PAP caused by GM-CSF receptor dysfunction due to Csf2rb mutations in mice.

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Shima, K. et al. Pulmonary macrophage transplantation therapy in Csf2ra gene-ablated mice: a novel model of hereditary pulmonary alveolar proteinosis in children. Am. J. Respir. Crit. Care Med. 195, A4857 (2017).

    Google Scholar 

  83. 83.

    Shima, K. et al. Development and validation of Csf2ra gene-deficient mice as a clinically relevant model of children with hereditary pulmonary alveolar ProteINOSis. Am. J. Respir. Crit. Care Med. 195, A4837 (2017).

    Google Scholar 

  84. 84.

    Nishinakamura, R. et al. The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation. J. Exp. Med. 183, 2657–2662 (1996).

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Suzuki, T. et al. Pulmonary macrophage transplantation therapy. Nature 514, 450–454 (2014). This report describes a novel approach to the therapy of hereditary PAP caused by Csf2rb mutations as well as the reciprocal feedback loop by which pulmonary GM-CSF regulates alveolar macrophage population size.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Willinger, T. et al. Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. Proc. Natl Acad. Sci. USA 108, 2390–2395 (2011).

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Nakamura, K. et al. Expression and regulation of multiple murine ATP-binding cassette transporter G1 mRNAs/isoforms that stimulate cellular cholesterol efflux to high density lipoprotein. J. Biol. Chem. 279, 45980–45989 (2004).

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Kennedy, M. A. et al. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 1, 121–131 (2005).

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Out, R. et al. Macrophage ABCG1 deletion disrupts lipid homeostasis in alveolar macrophages and moderately influences atherosclerotic lesion development in LDL receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 26, 2295–2300 (2006).

    CAS  Article  PubMed  Google Scholar 

  90. 90.

    Thomassen, M. J. et al. ABCG1 is deficient in alveolar macrophages of GM-CSF knockout mice and patients with pulmonary alveolar proteinosis. J. Lipid Res. 48, 2762–2768 (2007).

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Baker, A. D. et al. Targeted PPAR{gamma} deficiency in alveolar macrophages disrupts surfactant catabolism. J. Lipid Res. 51, 1325–1331 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Baker, A. D. et al. PPARgamma regulates the expression of cholesterol metabolism genes in alveolar macrophages. Biochem. Biophys. Res. Commun. 393, 682–687 (2010).

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Baldan, A. et al. Deletion of the transmembrane transporter ABCG1 results in progressive pulmonary lipidosis. J. Biol. Chem. 281, 29401–29410 (2006).

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    de Aguiar Vallim, T. Q. et al. ABCG1 regulates pulmonary surfactant metabolism in mice and men. J. Lipid Res. 58, 941–954 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Sakagami, T. et al. Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis. N. Engl. J. Med. 361, 2679–2681 (2009). This article demonstrates that GM-CSF autoantibodies were the cause of PAP and not an immune epiphenomenon.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Sakagami, T. et al. Patient-derived granulocyte/macrophage colony-stimulating factor autoantibodies reproduce pulmonary alveolar proteinosis in nonhuman primates. Am. J. Respir. Crit. Care Med. 182, 49–61 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Serrano, A. G. & Perez-Gil, J. Protein-lipid interactions and surface activity in the pulmonary surfactant system. Chem. Phys. Lipids. 141, 105–118 (2006).

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Orgeig, S. & Daniels, C. B. The roles of cholesterol in pulmonary surfactant: insights from comparative and evolutionary studies. Comp. Biochem. Physiol. A 129, 75–89 (2001).

    CAS  Article  Google Scholar 

  99. 99.

    Bernardino de la Serna, J., Perez-Gil, J., Simonsen, A. C. & Bagatolli, L. A. Cholesterol rules: direct observation of the coexistence of two fluid phases in native pulmonary surfactant membranes at physiological temperatures. J. Biol. Chem. 279, 40715–40722 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. 100.

    Yancey, P. G. & Jerome, W. G. Lysosomal sequestration of free and esterified cholesterol from oxidized low density lipoprotein in macrophages of different species. J. Lipid Res. 39, 1349–1361 (1998).

    CAS  PubMed  Google Scholar 

  101. 101.

    Kitamura, T. et al. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 190, 875–880 (1999). This article reports on the strong association of neutralizing GM-CSF autoantibodies with autoimmune PAP.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Tanaka, N. et al. Lungs of patients with idiopathic pulmonary alveolar proteinosis express a factor which neutralizes granulocyte-macrophage colony stimulating factor. FEBS Lett. 442, 246–250 (1999).

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Seymour, J. F. 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 58, 252–257 (2003). This article reports on the lack of correlation between GM-CSF autoantibody and disease severity in patients with autoimmune PAP.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Uchida, K. et al. High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood 103, 1089–1098 (2004).

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Bendtzen, K. et al. GM-CSF autoantibodies in pulmonary alveolar proteinosis. N. Engl. J. Med. 356, 2001–2002 (2007).

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Uchida, K. et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood 113, 2547–2556 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Sakagami, T., Suzuki, T., Carey, B., Chalk, C. & Trapnell, B. C. A novel assay to measure GM-CSF signaling in clinical blood specimens. Am. J. Respir. Crit. Care Med. 181, A2987 (2010).

    Google Scholar 

  108. 108.

    Meager, A. et al. Spontaneously occurring neutralizing antibodies against granulocyte-macrophage colony-stimulating factor in patients with autoimmune disease. Immunology 97, 526–532 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Uchida, K. et al. Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis. J. Immunol. Methods 402, 57–70 (2014). This article provides comprehensive data on serum GM-CSF autoantibody measurement, including data validating it as a novel sensitive and specific diagnostic test for autoimmune PAP.

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Wang, Y. et al. Characterization of pathogenic human monoclonal autoantibodies against GM-CSF. Proc. Natl Acad. Sci. USA 110, 7832–7837 (2013).

    CAS  Article  PubMed  Google Scholar 

  111. 111.

    Burmester, G. R. et al. Mavrilimumab, a fully human granulocyte-macrophage colony-stimulating factor receptor alpha monoclonal antibody: long-term safety and efficacy in patients with rheumatoid arthritis. Arthritis Rheumatol. 70, 679–689 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Piccoli, L. et al. Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. Nat. Commun. 6, 7375 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Griese, M. et al. Long-term follow-up and treatment of congenital alveolar proteinosis. BMC Pediatr. 11, 72 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Zhang, D. et al. Secondary pulmonary alveolar proteinosis: a single-center retrospective study (a case series and literature review). BMC Pulm. Med. 18, 15 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Griese, M. et al. GATA2 deficiency in children and adults with severe pulmonary alveolar proteinosis and hematologic disorders. BMC Pulm. Med. 15, 87 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Haworth, J. C., Hoogstraten, J. & Taylor, H. Thymic alymphoplasia. Arch. Dis. Child. 42, 40–54 (1967).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Yousem, S. A., Burke, C. M. & Billingham, M. E. Pathologic pulmonary alterations in long-term human heart-lung transplantation. Hum. Pathol. 16, 911–923 (1985).

    CAS  Article  PubMed  Google Scholar 

  118. 118.

    Nunes, V. & Niinikoski, H. Lysinuric protein intolerance. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1361/ (updated 12 Apr 2018).

  119. 119.

    Ceruti, M. et al. Successful whole lung lavage in pulmonary alveolar proteinosis secondary to lysinuric protein intolerance: a case report. Orphanet J. Rare Dis. 2, 14 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Enaud, L. et al. Pulmonary alveolar proteinosis in children on La Reunion Island: a new inherited disorder? Orphanet J. Rare Dis. 9, 85 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Hadchouel, A. et al. Biallelic mutations of methionyl-tRNA synthetase cause a specific type of pulmonary alveolar proteinosis prevalent on reunion island. Am. J. Hum. Genet. 96, 826–831 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Forbes, A. et al. Alveolar macrophage depletion is associated with increased surfactant pool sizes in adult rats. J. Appl. Physiol. 103, 637–645 (2007).

    CAS  Article  PubMed  Google Scholar 

  123. 123.

    Whitsett, J. A. & Weaver, T. E. Hydrophobic surfactant proteins in lung function and disease. N. Engl. J. Med. 347, 2141–2148 (2002).

    Article  PubMed  Google Scholar 

  124. 124.

    Ban, N. et al. ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J. Biol. Chem. 282, 9628–9634 (2007).

    CAS  Article  PubMed  Google Scholar 

  125. 125.

    Yusen, R. D., Cohen, A. H. & Hamvas, A. Normal lung function in subjects heterozygous for surfactant protein-B deficiency. Am. J. Respir. Crit. Care Med. 159, 411–414 (1999).

    CAS  Article  PubMed  Google Scholar 

  126. 126.

    Nogee, L. M. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu. Rev. Physiol. 66, 601–623 (2004).

    CAS  Article  PubMed  Google Scholar 

  127. 127.

    Cameron, H. S. et al. A common mutation in the surfactant protein C gene associated with lung disease. J. Pediatr. 146, 370–375 (2005).

    CAS  Article  PubMed  Google Scholar 

  128. 128.

    Nogee, L. M. Abnormal expression of surfactant protein C and lung disease. Am. J. Respir. Cell. Mol. Biol. 26, 641–644 (2002).

    CAS  Article  PubMed  Google Scholar 

  129. 129.

    Brasch, F. et al. Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am. J. Respir. Crit. Care Med. 174, 571–580 (2006).

    CAS  Article  PubMed  Google Scholar 

  130. 130.

    Kroner, C. et al. Lung disease caused by ABCA3 mutations. Thorax 72, 213–220 (2017).

    Article  PubMed  Google Scholar 

  131. 131.

    Garmany, T. H. et al. Surfactant composition and function in patients with ABCA3 mutations. Pediatr. Res. 59, 801–805 (2006).

    CAS  Article  PubMed  Google Scholar 

  132. 132.

    Devriendt, K., Vanhole, C., Matthijs, G. & de Zegher, F. Deletion of thyroid transcription factor-1 gene in an infant with neonatal thyroid dysfunction and respiratory failure. N. Engl. J. Med. 338, 1317–1318 (1998).

    CAS  Article  PubMed  Google Scholar 

  133. 133.

    Iwatani, N., Mabe, H., Devriendt, K., Kodama, M. & Miike, T. Deletion of NKX2.1 gene encoding thyroid transcription factor-1 in two siblings with hypothyroidism and respiratory failure. J. Pediatr. 137, 272–276 (2000).

    CAS  Article  PubMed  Google Scholar 

  134. 134.

    Clark, J. C. et al. Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice. Am. J. Respir. Cell. Mol. Biol. 16, 46–52 (1997).

    CAS  Article  PubMed  Google Scholar 

  135. 135.

    Lin, S. et al. Surfactant protein B (SP-B) -/- mice are rescued by restoration of SP-B expression in alveolar type II cells but not Clara cells. J. Biol. Chem. 274, 19168–19174 (1999).

    CAS  Article  PubMed  Google Scholar 

  136. 136.

    Glasser, S. W. et al. Pneumonitis and emphysema in sp-C gene targeted mice. J. Biol. Chem. 278, 14291–14298 (2003).

    CAS  Article  PubMed  Google Scholar 

  137. 137.

    Hammel, M. et al. Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies. Biochem. Biophys. Res. Commun. 359, 947–951 (2007).

    CAS  Article  PubMed  Google Scholar 

  138. 138.

    Jennings, V. M., Dillehay, D. L., Webb, S. K. & Brown, L. A. Pulmonary alveolar proteinosis in SCID mice. Am. J. Respir. Cell. Mol. Biol. 13, 297–306 (1995).

    CAS  Article  PubMed  Google Scholar 

  139. 139.

    Ikegami, M. et al. IL-4 increases surfactant and regulates metabolism in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L75–L80 (2000).

    CAS  Article  PubMed  Google Scholar 

  140. 140.

    Homer, R. J. et al. Pulmonary type II cell hypertrophy and pulmonary lipoproteinosis are features of chronic IL-13 exposure. Am. J. Physiol. Lung Cell. Mol. Physiol. 283, L52–L59 (2002).

    CAS  Article  PubMed  Google Scholar 

  141. 141.

    Botas, C. et al. Altered surfactant homeostasis and alveolar type II cell morphology in mice lacking surfactant protein D. Proc. Natl Acad. Sci. USA 95, 11869–11874 (1998).

    CAS  Article  PubMed  Google Scholar 

  142. 142.

    Agarwal, P. P., Seely, J. M., Perkins, D. G., Matzinger, F. R. & Alikhan, Q. Pulmonary alveolar proteinosis and end-stage pulmonary fibrosis: a rare association. J. Thorac. Imaging 20, 242–244 (2005).

    Article  PubMed  Google Scholar 

  143. 143.

    Ono, M. et al. Pathological features of explant lungs with fibrosis in autoimmune pulmonary alveolar proteinosis. Respirol. Case Rep. 5, e00255 (2017).

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Akira, M. et al. Pulmonary fibrosis on high-resolution CT of patients with pulmonary alveolar proteinosis. AJR Am. J. Roentgenol. 207, 544–551 (2016).

    Article  PubMed  Google Scholar 

  145. 145.

    Hunt, A. N. et al. Hepatic steatosis accompanies pulmonary alveolar proteinosis. Am. J. Respir. Cell. Mol. Biol. 57, 448–458 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Carey, B. & Trapnell, B. C. The molecular basis of pulmonary alveolar proteinosis. Clin. Immunol. 135, 223–235 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Bonella, F. et al. Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients. Respir. Med. 105, 1908–1916 (2011).

    Article  PubMed  Google Scholar 

  148. 148.

    McCarthy, C. et al. Differential diagnosis of pulmonary alveolar proteinosis: lung biopsy or blood test? Am. J. Respir. Crit. Care Med. 197, A1093 (2018).

    Article  Google Scholar 

  149. 149.

    Ganguli, P. C., Lynne-Davies, P. & Sproule, B. J. Pulmonary alveolar proteinosis, bronchiectasis and secondary amyloidosis: a case report. Can. Med. Assoc. J. 106, 569 (1972).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Nogee, L. M. Genetic basis of children’s interstitial lung disease. Pediatr. Allergy Immunol. Pulmonol. 23, 15–24 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Hamvas, A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: clinical features and evaluation. Semin. Perinatol. 30, 316–326 (2006).

    Article  PubMed  Google Scholar 

  152. 152.

    Campo, I. et al. Assessment and management of pulmonary alveolar proteinosis in a reference center. Orphanet J. Rare Dis. 8, 40 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Punatar, A. D., Kusne, S., Blair, J. E., Seville, M. T. & Vikram, H. R. Opportunistic infections in patients with pulmonary alveolar proteinosis. J. Infect. 65, 173–179 (2012).

    Article  PubMed  Google Scholar 

  154. 154.

    Selman, M. et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum. Genet. 113, 542–550 (2003).

    CAS  Article  PubMed  Google Scholar 

  155. 155.

    Goldstein, L. S. et al. Pulmonary alveolar proteinosis: clinical features and outcomes. Chest 114, 1357–1362 (1998).

    CAS  Article  PubMed  Google Scholar 

  156. 156.

    Lee, K. N. et al. Pulmonary alveolar proteinosis: high-resolution CT, chest radiographic, and functional correlations. Chest 111, 989–995 (1997).

    CAS  Article  PubMed  Google Scholar 

  157. 157.

    Johkoh, T. et al. Crazy-paving appearance at thin-section CT: spectrum of disease and pathologic findings. Radiology 211, 155–160 (1999).

    CAS  Article  PubMed  Google Scholar 

  158. 158.

    Ishii, H. et al. Comparative study of high-resolution CT findings between autoimmune and secondary pulmonary alveolar proteinosis. Chest 136, 1348–1355 (2009).

    Article  PubMed  Google Scholar 

  159. 159.

    Costabel, U., Guzman, J., Bonella, F. & Oshimo, S. Bronchoalveolar lavage in other interstitial lung diseases. Semin. Respir. Crit. Care Med. 28, 514–524 (2007).

    Article  PubMed  Google Scholar 

  160. 160.

    Bonella, F., Ohshimo, S., Bauer, P., Guzman, J. & Costabel, U. in Interventional pneumology: European Respiratory Society Monograph Vol. 48 Ch. 5 (eds Strausz, J. & Bolliger, C. T.) 59–72 (European Respiratory Society, 2010).

  161. 161.

    Presneill, J. J., Nakata, K., Inoue, Y. & Seymour, J. F. Pulmonary alveolar proteinosis. Clin. Chest Med. 25, 593–613 (2004).

    Article  PubMed  Google Scholar 

  162. 162.

    Fujishima, T., Honda, Y., Shijubo, N., Takahashi, H. & Abe, S. Increased carcinoembryonic antigen concentrations in sera and bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Respiration 62, 317–321 (1995).

    CAS  Article  PubMed  Google Scholar 

  163. 163.

    Arai, T. et al. Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF. Respir. Med. 98, 1227–1230 (2004).

    Article  PubMed  Google Scholar 

  164. 164.

    Fang, S. C., Lu, K. H., Wang, C. Y., Zhang, H. T. & Zhang, Y. M. Elevated tumor markers in patients with pulmonary alveolar proteinosis. Clin. Chem. Lab. Med. 51, 1493–1498 (2013).

    CAS  Article  PubMed  Google Scholar 

  165. 165.

    Takahashi, T., Munakata, M., Suzuki, I. & Kawakami, Y. Serum and bronchoalveolar fluid KL-6 levels in patients with pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 158, 1294–1298 (1998).

    CAS  Article  PubMed  Google Scholar 

  166. 166.

    Kuroki, Y. et al. Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis. Am. Rev. Respir. Dis. 147, 723–729 (1993).

    CAS  Article  PubMed  Google Scholar 

  167. 167.

    Seymour, J. F. et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am. J. Respir. Crit. Care Med. 163, 524–531 (2001).

    CAS  Article  PubMed  Google Scholar 

  168. 168.

    Iyonaga, K. et al. Elevated bronchoalveolar concentrations of MCP-1 in patients with pulmonary alveolar proteinosis. Eur. Respir. J. 14, 383–389 (1999).

    CAS  Article  PubMed  Google Scholar 

  169. 169.

    Bonella, F. et al. Serum YKL-40 is a reliable biomarker for pulmonary alveolar proteinosis. Respirology 22, 1371–1378 (2017).

    Article  PubMed  Google Scholar 

  170. 170.

    Sergeeva, A., Ono, Y., Rios, R. & Molldrem, J. J. High titer autoantibodies to GM-CSF in patients with AML, CML and MDS are associated with active disease. Leukemia 22, 783–790 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Han, X. et al. Granulocyte-macrophage colony-stimulating factor autoantibodies in murine ileitis and progressive ileal Crohn’s disease. Gastroenterology 136, 1261–1271 (2009).

    CAS  Article  PubMed  Google Scholar 

  172. 172.

    Carey, B. et al. Use of serum GM-CSF for diagnosis of patients with hereditary pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 187, A2850 (2013).

    Article  CAS  Google Scholar 

  173. 173.

    Kusakabe, Y. et al. A standardized blood test for the routine clinical diagnosis of impaired GM-CSF signaling using flow cytometry. J. Immunol. Methods. 413, 1–11 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Tredano, M. et al. Compound SFTPB 1549C→GAA (121ins2) and 457delC heterozygosity in severe congenital lung disease and surfactant protein B (SP-B) deficiency. Hum. Mutat. 14, 502–509 (1999).

    CAS  Article  PubMed  Google Scholar 

  175. 175.

    Griese, M. et al. Expression profiles of hydrophobic surfactant proteins in children with diffuse chronic lung disease. Respir. Res. 6, 80 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Tredano, M. et al. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am. J. Med. Genet. 126A, 18–26 (2004).

    Article  PubMed  Google Scholar 

  177. 177.

    Stevens, P. A. et al. Nonspecific interstitial pneumonia, alveolar proteinosis, and abnormal proprotein trafficking resulting from a spontaneous mutation in the surfactant protein C gene. Pediatr. Res. 57, 89–98 (2005).

    Article  PubMed  Google Scholar 

  178. 178.

    Saugstad, O. D. et al. Novel mutations in the gene encoding ATP binding cassette protein member A3 (ABCA3) resulting in fatal neonatal lung disease. Acta Paediatr. 96, 185–190 (2007).

    Article  PubMed  Google Scholar 

  179. 179.

    Leonidas, D. D. et al. The binding of 3′-N-piperidine-4-carboxyl-3′-deoxy-ara-uridine to ribonuclease A in the crystal. Bioorg. Med. Chem. 14, 6055–6064 (2006).

    CAS  Article  PubMed  Google Scholar 

  180. 180.

    Hamvas, A. et al. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 144, 794–804 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Xu, Z., Jing, J., Wang, H., Xu, F. & Wang, J. Pulmonary alveolar proteinosis in China: a systematic review of 241 cases. Respirology 14, 761–766 (2009).

    Article  PubMed  Google Scholar 

  182. 182.

    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. 31, 43–49 (2002).

    Article  PubMed  Google Scholar 

  183. 183.

    Wasserman, K., Blank, N. & Fletcher, G. Lung lavage (alveolar washing) in alveolar proteinosis. Am. J. Med. 44, 611–617 (1968).

    CAS  Article  PubMed  Google Scholar 

  184. 184.

    Beccaria, M. et al. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur. Respir. J. 23, 526–531 (2004). This article reports on the practice and utility of WLL therapy of PAP.

    CAS  Article  PubMed  Google Scholar 

  185. 185.

    Campo, I. et al. A global survey on whole lung lavage in pulmonary alveolar proteinosis. Chest 150, 251–253 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Selecky, P. A., Wasserman, K., Benfield, J. R. & Lippmann, M. The clinical and physiological effect of whole-lung lavage in pulmonary alveolar proteinosis: a ten-year experience. Ann. Thorac. Surg. 24, 451–461 (1977).

    CAS  Article  PubMed  Google Scholar 

  187. 187.

    Rogers, R. M., Levin, D. C., Gray, B. A. & Moseley, L. W. Jr. Physiologic effects of bronchopulmonary lavage in alveolar proteinosis. Am. Rev. Respir. Dis. 118, 255–264 (1978).

    CAS  PubMed  Google Scholar 

  188. 188.

    Campo, I. et al. Whole lung lavage therapy for pulmonary alveolar proteinosis: a global survey of current practices and procedures. Orphanet J. Rare Dis. 11, 115 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Eber, E. et al. ERS statement: interventional bronchoscopy in children. Eur. Respir. J. 50, 1700901 (2017).

    Article  PubMed  Google Scholar 

  190. 190.

    Reiter, K., Schoen, C., Griese, M. & Nicolai, T. Whole-lung lavage in infants and children with pulmonary alveolar proteinosis. Paediatr. Anaesth. 20, 1118–1123 (2010).

    Article  PubMed  Google Scholar 

  191. 191.

    Jansen, H. M., Zuurmond, W. W., Roos, C. M., Schreuder, J. J. & Bakker, D. J. Whole-lung lavage under hyperbaric oxygen conditions for alveolar proteinosis with respiratory failure. Chest 91, 829–832 (1987).

    CAS  Article  PubMed  Google Scholar 

  192. 192.

    Cohen, E. S., Elpern, E. & Silver, M. R. Pulmonary alveolar proteinosis causing severe hypoxemic respiratory failure treated with sequential whole-lung lavage utilizing venovenous extracorporeal membrane oxygenation: a case report and review. Chest 120, 1024–1026 (2001).

    CAS  Article  PubMed  Google Scholar 

  193. 193.

    Sadeghi, H. A. Segmental lung lavage with fiberoptic bronchoscopy in a patient with special presentation of pulmonary alveolar proteinosis. Tanaffos 12, 48–52 (2013).

    PubMed  PubMed Central  Google Scholar 

  194. 194.

    King, T. E. Jr. et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2083–2092 (2014).

    Article  CAS  PubMed  Google Scholar 

  195. 195.

    Richeldi, L. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2071–2082 (2014).

    Article  CAS  PubMed  Google Scholar 

  196. 196.

    Albores, J. et al. A rare occurrence of pulmonary alveolar proteinosis after lung transplantation. Semin. Respir. Crit. Care Med. 34, 431–438 (2013).

    Article  PubMed  Google Scholar 

  197. 197.

    Takaki, M. et al. Recurrence of pulmonary alveolar proteinosis after bilateral lung transplantation in a patient with a nonsense mutation in CSF2RB. Respir. Med. Case Rep. 19, 89–93 (2016).

    PubMed  PubMed Central  Google Scholar 

  198. 198.

    Parker, L. A. & Novotny, D. B. Recurrent alveolar proteinosis following double lung transplantation. Chest 111, 1457–1458 (1997).

    CAS  Article  PubMed  Google Scholar 

  199. 199.

    Santamaria, F. et al. Recurrent fatal pulmonary alveolar proteinosis after heart-lung transplantation in a child with lysinuric protein intolerance. J. Pediatr. 145, 268–272 (2004).

    Article  PubMed  Google Scholar 

  200. 200.

    Palomar, L. M. et al. Long-term outcomes after infant lung transplantation for surfactant protein B deficiency related to other causes of respiratory failure. J. Pediatr. 149, 548–553 (2006).

    Article  PubMed  Google Scholar 

  201. 201.

    Hamvas, A. et al. Lung transplantation for treatment of infants with surfactant protein B deficiency. J. Pediatr. 130, 231–239 (1997).

    CAS  Article  PubMed  Google Scholar 

  202. 202.

    Seymour, J. F., Dunn, A. R., Vincent, J. M., Presneill, J. J. & Pain, M. C. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis. N. Engl. J. Med. 335, 1924–1925 (1996).

    CAS  Article  PubMed  Google Scholar 

  203. 203.

    Venkateshiah, S. B. et al. An open-label trial of granulocyte macrophage colony stimulating factor therapy for moderate symptomatic pulmonary alveolar proteinosis. Chest 130, 227–237 (2006).

    CAS  Article  PubMed  Google Scholar 

  204. 204.

    Wylam, M. E. et al. Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur. Respir. J. 27, 585–593 (2006).

    CAS  Article  PubMed  Google Scholar 

  205. 205.

    Papiris, S. A. et al. Long-term inhaled granulocyte macrophage-colony-stimulating factor in autoimmune pulmonary alveolar proteinosis: effectiveness, safety, and lowest effective dose. Clin. Drug Investig. 34, 553–564 (2014).

    CAS  Article  PubMed  Google Scholar 

  206. 206.

    Tazawa, R. et al. Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 171, 1142–1149 (2005).

    Article  PubMed  Google Scholar 

  207. 207.

    Tazawa, R. et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 181, 1345–1354 (2010). This article reports results from a clinical trial of inhaled GM-CSF therapy for autoimmune PAP.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Tazawa, R. et al. Duration of benefit in patients with autoimmune pulmonary alveolar proteinosis after inhaled granulocyte-macrophage colony-stimulating factor therapy. Chest 145, 729–737 (2014).

    CAS  Article  PubMed  Google Scholar 

  209. 209.

    Tazawa, R., Nakata, K., Inoue, Y. & Nukiwa, T. Granulocyte-macrophage colony-stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long-term treatment with aerosolized granulocyte-macrophage colony-stimulating factor: a case report. Respirology 11 (Suppl.), 61–64 (2006).

    Article  Google Scholar 

  210. 210.

    Ohashi, K. et al. Direct evidence that GM-CSF inhalation improves lung clearance in pulmonary alveolar proteinosis. Respir. Med. 106, 284–293 (2012).

    Article  PubMed  Google Scholar 

  211. 211.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02702180 (2018).

  212. 212.

    Kavuru, M. S., Bonfield, T. L. & Thomassen, M. J. Plasmapheresis, GM-CSF, and alveolar proteinosis. Am. J. Respir. Crit. Care Med. 167, 1036 (2003).

    Article  PubMed  Google Scholar 

  213. 213.

    Akasaka, K. et al. Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study. BMC Pulm. Med. 15, 88 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. 214.

    Kavuru, M. S. et al. An open-label trial of rituximab therapy in pulmonary alveolar proteinosis. Eur. Respir. J. 38, 1361–1367 (2011).

    CAS  Article  PubMed  Google Scholar 

  215. 215.

    Amital, A., Dux, S., Shitrit, D., Shpilberg, O. & Kramer, M. R. Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis. Thorax 65, 1025–1026 (2010).

    Article  PubMed  Google Scholar 

  216. 216.

    Borie, R., Debray, M. P., Laine, C., Aubier, M. & Crestani, B. Rituximab therapy in autoimmune pulmonary alveolar proteinosis. Eur. Respir. J. 33, 1503–1506 (2009).

    CAS  Article  PubMed  Google Scholar 

  217. 217.

    Malur, A. et al. Rituximab therapy in pulmonary alveolar proteinosis improves alveolar macrophage lipid homeostasis. Respir. Res. 13, 46 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  218. 218.

    Soyez, B. et al. Rituximab for auto-immune alveolar proteinosis, a real life cohort study. Respir. Res. 19, 74 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. 219.

    Kleff, V. et al. Gene therapy of beta(c)-deficient pulmonary alveolar proteinosis (beta(c)-PAP): studies in a murine in vivo model. Mol. Ther. 16, 757–764 (2008).

    CAS  Article  PubMed  Google Scholar 

  220. 220.

    Fremond, M. L. et al. Successful haematopoietic stem cell transplantation in a case of pulmonary alveolar proteinosis due to GM-CSF receptor deficiency. Thorax 73, 590–592 (2018).

    Article  PubMed  Google Scholar 

  221. 221.

    Tabata, S. et al. Successful allogeneic bone marrow transplantation for myelodysplastic syndrome complicated by severe pulmonary alveolar proteinosis. Int. J. Hematol. 90, 407–412 (2009).

    Article  PubMed  Google Scholar 

  222. 222.

    Pidala, J., Khalil, F. & Fernandez, H. Pulmonary alveolar proteinosis following allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 46, 1480–1483 (2011).

    CAS  Article  PubMed  Google Scholar 

  223. 223.

    Lachmann, N. et al. Gene correction of human induced pluripotent stem cells repairs the cellular phenotype in pulmonary alveolar proteinosis. Am. J. Respir. Crit. Care Med. 189, 167–182 (2014).

    CAS  PubMed  Google Scholar 

  224. 224.

    Suzuki, T. et al. Use of induced pluripotent stem cells to recapitulate pulmonary alveolar proteinosis pathogenesis. Am. J. Respir. Crit. Care Med. 189, 183–193 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. 225.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03231033 (2017).

  226. 226.

    Ware, J. E. Jr & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care. 30, 473–483 (1992).

    Article  PubMed  Google Scholar 

  227. 227.

    Ohkouchi, S. et al. Sequential granulocyte-macrophage colony-stimulating factor inhalation after whole-lung lavage for pulmonary alveolar proteinosis. A report of five intractable cases. Ann. Am. Thorac Soc. 14, 1298–1304 (2017).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the US National Heart Lung and Blood Institute (NHLBI) (R01 HL085453 to B.C.T.); the US National Center for Advancing Translational Sciences (NCATS)/NHLBI (U54 HL127672 to B.C.T.); the Japanese Agency for Medical Research and Development (JP17ek0109079h0003 to K.N.) and the Australian National Health and Medical Research Council (to J.H.).

Reviewer information

Nature Reviews Disease Primers thanks M. Hetzel and the other anonymous reviewer(s), for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

Introduction (I.C.); Epidemiology (K.N.); Mechanisms/pathophysiology (B.C.T. and J.H.); Diagnosis, screening and prevention (F.B. and C.Mc.); Management (C.Mo. and M.G.); Quality of life (T.W.); Outlook (V.C.); Overview of Primer (B.C.T.).

Corresponding author

Correspondence to Bruce C. Trapnell.

Ethics declarations

Competing interests

All authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

EuPAPNet: http://www.alveolarproteinosis.eu/

PAP Foundation: http://www.papfoundation.org/

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Trapnell, B.C., Nakata, K., Bonella, F. et al. Pulmonary alveolar proteinosis. Nat Rev Dis Primers 5, 16 (2019). https://doi.org/10.1038/s41572-019-0066-3

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing